EP2788086B1 - Substituted pyrazoles as mglu5 receptor modulators - Google Patents

Substituted pyrazoles as mglu5 receptor modulators Download PDF

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EP2788086B1
EP2788086B1 EP12808705.3A EP12808705A EP2788086B1 EP 2788086 B1 EP2788086 B1 EP 2788086B1 EP 12808705 A EP12808705 A EP 12808705A EP 2788086 B1 EP2788086 B1 EP 2788086B1
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added
acid
stirred
desired product
reaction
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EP2788086A1 (en
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Matthias Grauert
Daniel Bischoff
Georg Dahmann
Raimund Kuelzer
Klaus Rudolf
Bernd Wellenzohn
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Boehringer Ingelheim International GmbH
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    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • Glutamate is the primary excitatory amino acid in the mammalian central nervous system. Neurotransmission mediated by glutamate has been demonstrated to be critical in many physiological processes, such as synaptic plasticity, long term potentiation involved in both learning and memory as well as sensory perception ( Riedel et al., Behav. Brain Res. 2003, 140:1-47 ). Furthermore, it has been demonstrated that an imbalance of glutamate neurotransmission plays a critical role in the pathophysiology of various neurological and psychiatric diseases.
  • the excitatory neurotransmission of glutamate is mediated through at least two different classes of receptors, the ionotropic glutamate receptors (NMDA, AMPA and kainate) and the metabotropic glutamate receptors (mGluR).
  • the ionotropic receptors are ligand gated ion channels and are thought to be responsible for the regulating rapid neuronal transmission between two neurons.
  • the metabotropic glutamate receptors are G-protein coupled receptors (GPCRs) which appear to mediate not only synaptic transmission, but also to regulate the extent of neurotransmitter release as well as post synaptic receptor activation.
  • mGluR5 belongs to a superfamily of currently eight identified Type III GPCRs, which are unique in that the glutamate ligand binds to a large extracellular amino-terminal protein domain. This superfamily is further divided into three gropus (Group I, II and III) based on amino acid homology as well as the intracellular signalling cascades they regulate ( Schoepp et al., Neuropharma, 1999, 38:1431-1476 ).
  • mGluR5 belongs to group I and is coupled to the phospholipase C signalling cascade which regulates intracellular calcium mobilization.
  • CNS mGluR5 has been demonstrared to be expressed mainly in the cortex, hippocampus, nucleus accumbens and the caudate-putamen. These brain regions are known to be involved in memory formation and cogntive function as well as emotional response.
  • mGluR5 has been shown to be localized post-synaptically, adjacent to the post-synaptic density ( Lujan et al., Eur. J. Neurosci. 1996, 8: 1488-1500 ).
  • mGluR5 A functional interaction between mGluR5 and the NMDA receptor has also been demonstrated, where activation of mGluR5 potentiates the activation state of the NMDA receptor ( Mannaioni et al, NeuroSci., 2001, 21:5925-5924 , Rosenbrock et al., Eur. J. Pharma., 2010, 639:40-46 ). Furthermore, activation of mGluR5 has been demonstrated in pre-clinical in vivo models to rescue cognitive impairment as well as psychotic disturbance induced by NMDA receptor antagonists ( Chan et al., Psychopharma. 2008, 198:141-148 ).
  • mGluR5 activation of mGluR5, and thereby potentiation or normalization of the NMDA receptor signaling, is a potential mechanism for the treatment of psychiatric and neurological disorders.
  • Most agonists of mGluR5 bind the orthosteric glutamate binding site. Since the glutamate binding site between the mGluR family members is highly conserved, it has been challenging to develop selective mGluR5 agonists which have acceptable CNS penetration and demonstrate in vivo activity.
  • An alternative approach to achieve selectivity between the mGluR family members is to develop compounds which bind to an allosteric site, which is not as highly conserved between the family members. These allosteric binding compounds would not interfere with the natural glutamate binding and signaling, but modulate the receptor activation state.
  • mGluR5 positive allosteric modulators of mGluR5 have recently been identified ( O'Brien et al., Mol. Pharma. 2003, 64: 731-740 , Lindsley et al., J. Med. Chem 2004, 47: 5825-5828 ). These compounds potentiate mGluR5 activity in the presence of bound glutamate. In the absence of bound glutamate, the mGluR5 positive modulators do not demonstrate intrinsic activity. Therefore, these compounds potentiate the natural signaling of mGluR5 as opposed to agonists which activate the receptor in a permanent, unnatural manner. mGluR5 positive allosteric modulators therefore represent an approach to potentiate mGluR5 signaling which in turn potentiates and normalizes the NMDA receptor hypofunction detected in neurological and psychiatric disorders.
  • WO 03/051833 discloses heteroaryl substitued pyrazoles which are shown to be mGluR5 inhibitors.
  • the present invention is directed to compounds of formula I in which
  • C 1-6 -alkyl means an alkyl group or radical having 1 to 6 carbon atoms.
  • the last named subgroup is the radical attachment point, for example, the substituent "aryl-C 1-3 -alkyl-" means an aryl group which is bound to a C 1-3 -alkyl-group, the latter of which is bound to the core or to the group to which the substituent is attached.
  • An asterisk is may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined.
  • the numeration of the atoms of a substituent starts with the atom which is closest to the core or to the group to which the substituent is attached.
  • 3-carboxypropyl-group represents the following substituent: wherein the carboxy group is attached to the third carbon atom of the propyl group.
  • the terms "1-methylpropyl-", “2,2-dimethylpropyl-” or “cyclopropylmethyl-” group represent the following groups:
  • the asterisk may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined.
  • a given chemical formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers etc%) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates including solvates of the free compounds or solvates of a salt of the compound.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • such salts include salts from ammonia, L-arginine, betaine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine (2,2'-iminobis(ethanol)), diethylamine, 2-(diethylamino)-ethanol, 2-aminoethanol, ethylenediamine, N-ethyl-glucamine, hydrabamine, 1H-imidazole, lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine (2,2',2"-nitrilotris(ethanol)), tromethamine, zinc hydroxide, acetic acid, 2.2-dichloro-acetic acid, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid,
  • salts can be formed with cations from metals like aluminium, calcium, lithium, magnesium, potassium, sodium, zinc and the like. (also see Pharmaceutical salts, Berge, S.M. et al., J. Pharm. Sci., (1977), 66, 1-19 ).
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof.
  • Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention e.g. trifluoro acetate salts, also comprise a part of the invention.
  • halogen generally denotes fluorine, chlorine, bromine and iodine.
  • C 1-8 -alkyl either alone or in combination with another radical denotes an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms.
  • C 1-5 -alkyl embraces the radicals H 3 C-, H 3 C-CH 2 -, H 3 C-CH 2 -CH 2 -, H 3 C-CH(CH 3 )-, H 3 C-CH 2 -CH 2 -CH 2 -, H 3 C-CH 2 -CH(CH 3 )-, H 3 C-CH(CH 3 )-CH 2 -, H 3 C-C(CH 3 ) 2 -, H 3 C-CH 2 -CH 2 -CH 2 -CH 2 -, H 3 C-CH 2 -CH 2 -CH(CH 3 )-, H 3 C-CH 2 -CH(CH 3 )-, H 3 C-CH 2 -CH(CH 3 )-CH 2 -, H 3 C-CH(CH 3 )-CH 2 -
  • C 2-n -alkenyl is used for a group as defined in the definition for "C 1-n -alkyl” with at least two carbon atoms, if at least two of those carbon atoms of said group are bonded to each other by a double bond.
  • C 3-7 -cycloalkyl either alone or in combination with another radical denotes a cyclic, saturated, unbranched hydrocarbon radical with 3 to n C atoms.
  • C 3-7 -cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • aryl denotes a carbocyclic aromatic monocyclic group containing 6 carbon atoms which may be further fused to a second 5- or 6-membered carbocyclic group which may be aromatic, saturated or unsaturated.
  • Aryl includes, but is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl and dihydronaphthyl.
  • heteroaryl is intended to include all the possible isomeric forms.
  • heteroaryl includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:
  • Aryl ketones were deprotonated with with potassium tert butoxide and condensed with a methylesters to form a di- keton.Then, the di-keton was condensed with hydrazine to yield a pyrazole-system.
  • the pyrazoles were coupled with 2-bromoacetic acid methyl ester under basic conditions to yield the desired pyrazol-1-yl-acetic acid methyl ester together with different quantities of the isomeric systhem.
  • the pyrazol-1-yl-acetic acid methyl ester was hydrolyzed with LiOH to the coresponding acid. The isomeres were either seperated before ore after hydrolysis of the ester.
  • the pyrazol-1-yl-acetic acides were coupled with an amine to the desired products.
  • the positive modulation of mGluR5 is measured in a HEK 293 cell line expressing human recombinant mGluR5 and is detected with calcium based FLIPR assay.
  • the cells are cultured with DMEM supplemented with 10% FCS, 2 ⁇ g/mL tetracycline, 100 ⁇ g/mL hygromycin and 500 ⁇ /mL gneticin.
  • the cell culture media is exchanged for tetracycline-free cell culture media 3-7 days before the assay.
  • One day before the assay the cell culture medium is exchanged to DMEM without glutamine and phenol red and supplemented with 10% FCS, 100 ⁇ /mL hygromycin and 500 ⁇ /mL geneticin.
  • the medium of the subconfluent cultures is removed and the cells are detached by addition of 2.5 ml EDTA(0.02%) per 175 cm2 culture flask for 1 minute.
  • the cells are resuspend in Ringer solution (140 mM NaCl, 5 mM KCl 2.5 mM CaCl2, 1.5 mM MgCl2, 5 mM Glucose, 10 mM Hepes; adjusted to pH 7.4 with NaOH), pooled and Ringer solution added to adjust the volume to 50 mL.
  • the cell suspension is centrifuged for 5 min at 1500U/min (425g).
  • the supernatant is removed and the cells washed a second time with 50 ml fresh Ringer solution and centrifuged again as before. The supernatant is again removed and the pellet resuspended in Ringer solution to 1,000,000cells/ml (1x10 ⁇ 6 cells / mL).
  • the cells are plated onto BD BioCoat Poly-D-Lysine 384 well plates (20.000 cells/well; 20 ⁇ l/well). The lid covered plates are then incubated until use at 37°C/10% CO2.
  • 20 ⁇ l of Calcium-4 assay kit solution (prepared according to the manufacturer's description in Ringer solution) are added to the cells and the plates are incubated for 80 min 37°C and then 10 min at room temperature.
  • Test compounds are dissolved and diluted in DMSO to 100-fold the desired concentrations.
  • the compounds are diluted in Ringer solution such that the compounds are 4-fold more concentrated than the desired final assay concentration.
  • the final DMSO concentration was 1%.
  • the peak height of the Ca release related fluorescence signal (9-66) is used for the EC50.
  • the EC50 of the modulation is calculated over a nonlinear regression with GraphPad Prism (Table 1). Table 1 Example EC50 [nM] Example EC50 [nM] Example EC50 [nM] Example EC50 [nM] 7.01.001 1429 7.01.080 277 7.02.061 96 7.02.139 101 7.01.002 592 7.01.081 30 7.02.062 323 7.02.140 51 7.01.003 1785 7.01.082 66 7.02.063 1728 7.02.141 138 7.01.004 390 7.01.083 86 7.02.064 177 7.02.142 27 7.01.005 381 7.01.084 34 7.02.065 194 7.02.143 48 7.01.006 870 7.01.085 26 7.02.066 24 7.02.144 68 7.01.007 1539 7.01.086 274 7.02.067 6 7.02.145 15 7.01.008 1184 7.01.087 125 7.02.068
  • the present invention is directed to compounds of general formula I which are useful in the treatment of a disease and/or condition wherein the activity of an mGluR5 positive modulator is of therapeutic benefit, including but not limited to the treatment of psychotic disorders, cognitive disorders and dementias.
  • the compounds of general formula I are useful for the treatment of psychotic disorders including schizophrenia, schizoaffective disorder and substance induced psychotic disorder; cognitive disorders and dementias including age-associated learning and memory impairments or losses, post stroke dementia, deficits in concentration, mild cognitive impairment, the cognitive dysfunction in Alzheimers disease, and the cognitive dysfunction of schizophrenia.
  • the present invention also relates to a compound of general formula I as a medicament.
  • a further aspect of the present invention relates to a compound of general formula I for the use in the treatment of a disease and/or condition wherein the activity of mGluR5 positive modulator is of therapeutic benefit.
  • the present invention relates to a compound of general formula I for the use in the treatment of psychotic disorders, cognitive disorders and dementias.
  • the present invention relates to a compound of general formula I for the use in the treatment of psychotic disorders including schizophrenia, schizoaffective disorder and substance induced psychotic disorder; cognitive disorders and dementias including age-associated learning and memory impairments or losses, post stroke dementia, deficits in concentration, mild cognitive impairment, the cognitive dysfunction in Alzheimers disease, and the cognitive dysfunction of schizophrenia.
  • the present disclosure relates to methods for the treatment or prevention of above mentioned diseases and conditions, which method comprises the administration of an effective amount of a compound of general formula I to a human being.
  • the dose range of the compounds of general formula I applicable per day is usually from 0.1 to 5000 mg, preferably from 0.1 to 1000 mg, more preferably from 5 to 500 mg, most preferably, 10 or 100 mg.
  • Each dosage unit may conveniently contain from 0.1 to 500 mg, preferably 10 to 100 mg.
  • the actual pharmaceutically effective amount or therapeutic dosage will of course depend on factors known by those skilled in the art such as age and weight of the patient, route of administration and severity of disease. In any case the combination will be administered at dosages and in a manner which allows a pharmaceutically effective amount to be delivered based upon patient's unique condition.
  • Suitable preparations for administering the compounds of formula will be apparent to those with ordinary skill in the art and include for example tablets, pills, capsules, suppositories, lozenges, troches, solutions, syrups, elixirs, sachets, injectables, inhalatives and powders etc.
  • the content of the pharmaceutically active compound(s) should be in the range from 1 to 99 wt.-%, preferably 10 to 90 wt.-%, more preferably 20 to 70 wt.-%, of the composition as a whole.
  • Suitable tablets may be obtained, for example, by mixing one or more compounds according to formula I with known excipients, for example inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and/or lubricants.
  • excipients for example inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and/or lubricants.
  • the tablets may also consist of several layers.
  • a further aspect of the invention is a pharmaceutical formulation including a compound of formula I in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the present invention relates to a combination therapy in which an active compound according to the present invention is administered together with another active compound.
  • the invention also refers to pharmaceutical formulations that provide such a combination of active ingredients, whereby one of which is an active compound of the present invention.
  • Such combinations may be fixed dose combinations (the active ingredients that are to be combined are subject of the same pharmaceutical formulation) or free dose combinations (active ingredients are in separate pharmaceutical formulations).
  • a further aspect of the present invention refers to a combination of each of the active compounds of the present invention, preferably at least one active compound according to the present invention, with another active compound for example selected from the group of antipsychotics such as haloperidol, clozapine, risperidone, quetiapine, aripripazole, and olanzapine; antidepressants such as selective serotonin re-uptake inhibitors and dual serotonin/noradrenaline re-uptake inhibitors; mood stabilizers such as lithium valproate and lamotrigine; beta-secretase inhibitors; gamma-secretase inhibitors; gamma-secretase modulators; amyloid aggregation inhibitors such as e.g.
  • scyllo-inositol directly or indirectly acting neuroprotective and/or disease-modifying substances; anti-oxidants, such as e.g. vitamin E , ginko biloba or ginkolide; anti-inflammatory substances, such as e.g. Cox inhibitors, NSAIDs additionally or exclusively having Aß (Abeta) lowering properties; HMG-CoA reductase inhibitors, such as statins; acetylcholine esterase inhibitors, such as donepezil, rivastigmine, tacrine, galantamine; NMDA receptor antagonists such as e.g.
  • anti-oxidants such as e.g. vitamin E , ginko biloba or ginkolide
  • anti-inflammatory substances such as e.g. Cox inhibitors, NSAIDs additionally or exclusively having Aß (Abeta) lowering properties
  • HMG-CoA reductase inhibitors such as statins
  • AMPA receptor agonists AMPA receptor positive modulators
  • AMPkines glycine transporter 1 inhibitors
  • monoamine receptor reuptake inhibitors substances modulating the concentration or release of neurotransmitters; substances inducing the secretion of growth hormone such as ibutamoren mesylate and capromorelin; CB-1 receptor antagonists or inverse agonists; antibiotics such as minocyclin or rifampicin; PDE1, PDE2, PDE4, PDE5, PDE9 or PDE10 inhibitors, GABAA receptor inverse agonists; GABAA alpha5 receptor inverse agonists; GABAA receptor antagonists; nicotinic receptor agonists or partial agonists or positive modulators; alpha4beta2 nicotinic receptor agonists or partial agonists or positive modulators; alpha7 nicotinic receptor agonists or partial agonists; histamine receptor H3 antagonists; 5-HT4 receptor agonists or partial agonists;
  • the active compounds according to the invention may also be used in combination with immunotherapies such as e.g. active immunisation with Abeta or parts thereof or passive immunisation with humanised anti-Abeta antibodies, nanobodies or antibody fragments for the treatment of the above mentioned diseases and conditions.
  • immunotherapies such as e.g. active immunisation with Abeta or parts thereof or passive immunisation with humanised anti-Abeta antibodies, nanobodies or antibody fragments for the treatment of the above mentioned diseases and conditions.
  • the active compounds according to the invention also may be combined with antipsychotics like haloperidol, flupentixol, fluspirilene, chlorprothixene, prothipendyl, levomepromazine, clozapine, olanzapine, quetiapine, risperidone, paliperidone, amisulpride, ziprasidone, aripiprazol, sulpiride, zotepine, sertindole, fluphenazine, perphenazine, perazine, promazine, chlorpromazine, levomepromazine, benperidol, bromperidol, pimozid, melperone, pipamperone, iloperidone, asenapine, perospirone, blonanserin, lurasidone.
  • antipsychotics like haloperidol, flupentixol, fluspirilene, chlorprothixene,
  • the active compounds according to the invention also may be combined with antidepressants like amitriptyline imipramine hydrochloride, imipramine maleate, lofepramine, desipramine, doxepin, trimipramine.
  • antidepressants like amitriptyline imipramine hydrochloride, imipramine maleate, lofepramine, desipramine, doxepin, trimipramine.
  • the active compounds according to the invention also may be combined with serotonin (5-HT) reuptake inhibitors such as alaproclate, citalopram escitalopram, clomipramine, duloxetine, femoxetine, fenfluramine, norfenfluramine, fluoxetine, fluvoxamine, indalpine, milnacipran, paroxetine, sertraline, trazodone, venlafaxine, zimelidine, bicifadine, desvenlafaxine, brasofens
  • the combinations according to the present invention may be provided simultaneously in one and the same dosage form, i.e. in form of a combination preparation, for example the two components may be incorporated in one tablet, e. g. in different layers of said tablet.
  • the combination may be also provided separately, in form of a free combination, i.e. the active compounds of the present invention are provided in one dosage form and one or more of the above mentioned combination partners is provided in another dosage form.
  • These two dosage forms may be equal dosage forms, for example a co-administration of two tablets, one containing a therapeutically effective amount of the active compound of the present invention and one containing a therapeutically effective amount of the above mentioned combination partner. It is also possible to combine different administration forms, if desired. Any type of suitable administration forms may be provided.
  • the active compound according to the invention, or a physiologically acceptable salt thereof, in combination with another active substance may be used simultaneously or at staggered times, but particularly close together in time. If administered simultaneously, the two active substances are given to the patient together; if administered at staggered times the two active substances are given to the patient successively within a period of less than or equal to 12, particularly less than or equal to 6 hours.
  • the dosage or administration forms are not limited, in the frame of the present invention any suitable dosage form may be used.
  • the dosage forms may be selected from solid preparations such as patches, tablets, capsules, pills, pellets, dragees, powders, troches, suppositories, liquid preparations such as solutions, suspensions, emulsions, drops, syrups, elixirs, or gaseous preparations such as aerosols, sprays and the like.
  • the dosage forms are advantageously formulated in dosage units, each dosage unit being adapted to supply a single dose of each active component being present. Depending from the administration route and dosage form the ingredients are selected accordingly.
  • the dosage for the above-mentioned combination partners may be expediently 1/5 of the normally recommended lowest dose up to 1/1 of the normally recommended dose.
  • the dosage forms are administered to the patient for example 1, 2, 3, or 4 times daily depending on the nature of the formulation. In case of retarding or extended release formulations or other pharmaceutical formulations, the same may be applied differently (e.g. once weekly or monthly etc.). It is preferred that the active compounds of the invention be administered either three or fewer times, more preferably once or twice daily.

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Description

    Field of the invention
  • Disclosed are substituted pyrazoles and their use as positive allosteric modulators of mGlu5 receptor activity, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of neurological and psychiatric disorders associated with glutamate dysfunction such as schizophrenia or cognitive decline such as dementia or cognitive impairment.
    • Background of the invention
  • Glutamate is the primary excitatory amino acid in the mammalian central nervous system. Neurotransmission mediated by glutamate has been demonstrated to be critical in many physiological processes, such as synaptic plasticity, long term potentiation involved in both learning and memory as well as sensory perception (Riedel et al., Behav. Brain Res. 2003, 140:1-47). Furthermore, it has been demonstrated that an imbalance of glutamate neurotransmission plays a critical role in the pathophysiology of various neurological and psychiatric diseases.
  • The excitatory neurotransmission of glutamate is mediated through at least two different classes of receptors, the ionotropic glutamate receptors (NMDA, AMPA and kainate) and the metabotropic glutamate receptors (mGluR). The ionotropic receptors are ligand gated ion channels and are thought to be responsible for the regulating rapid neuronal transmission between two neurons. The metabotropic glutamate receptors are G-protein coupled receptors (GPCRs) which appear to mediate not only synaptic transmission, but also to regulate the extent of neurotransmitter release as well as post synaptic receptor activation.
  • Disregulation in glutamatergic neurotransmission, for example through altered glutamate release or post-synaptic receptor activation, has been demonstrated in a variety of neurological ans well as psychiatric disorders. Hypofunction of the NMDA receptor has not only been demonstrated in Alzheimer's patients, but is increasingly accepted as the putative cause of schizophrenia (Farber et al., Prog. Brain Res., 1998, 116: 421-437, Coyle et al., Cell. and Mol Neurobiol. 2006, 26: 365-384). This is supported by clinical studies showing that antagonists of the NMDA receptor induce symptoms indistinguishable to those suffered by schizophrenia patients (Javitt et al., Am J. Psychiatry, 1991, 148: 1301-1308). Therefore, approaches that could potentiate or normalize NMDA receptor signallng have the potential to treat neurological and psychiatric disorders. mGluR5 belongs to a superfamily of currently eight identified Type III GPCRs, which are unique in that the glutamate ligand binds to a large extracelullar amino-terminal protein domain. This superfamily is further divided into three gropus (Group I, II and III) based on amino acid homology as well as the intracellular signalling cascades they regulate (Schoepp et al., Neuropharma, 1999, 38:1431-1476). mGluR5 belongs to group I and is coupled to the phospholipase C signalling cascade which regulates intracellular calcium mobilization. In the CNS, mGluR5 has been demonstrared to be expressed mainly in the cortex, hippocampus, nucleus accumbens and the caudate-putamen. These brain regions are known to be involved in memory formation and cogntive function as well as emotional response. mGluR5 has been shown to be localized post-synaptically, adjacent to the post-synaptic density (Lujan et al., Eur. J. Neurosci. 1996, 8: 1488-1500). A functional interaction between mGluR5 and the NMDA receptor has also been demonstrated, where activation of mGluR5 potentiates the activation state of the NMDA receptor (Mannaioni et al, NeuroSci., 2001, 21:5925-5924, Rosenbrock et al., Eur. J. Pharma., 2010, 639:40-46). Furthermore, activation of mGluR5 has been demonstrated in pre-clinical in vivo models to rescue cognitive impairment as well as psychotic disturbance induced by NMDA receptor antagonists (Chan et al., Psychopharma. 2008, 198:141-148). Therefore, activation of mGluR5, and thereby potentiation or normalization of the NMDA receptor signaling, is a potential mechanism for the treatment of psychiatric and neurological disorders. Most agonists of mGluR5 bind the orthosteric glutamate binding site. Since the glutamate binding site between the mGluR family members is highly conserved, it has been challenging to develop selective mGluR5 agonists which have acceptable CNS penetration and demonstrate in vivo activity. An alternative approach to achieve selectivity between the mGluR family members is to develop compounds which bind to an allosteric site, which is not as highly conserved between the family members. These allosteric binding compounds would not interfere with the natural glutamate binding and signaling, but modulate the receptor activation state. Positive allosteric modulators of mGluR5 have recently been identified (O'Brien et al., Mol. Pharma. 2003, 64: 731-740, Lindsley et al., J. Med. Chem 2004, 47: 5825-5828). These compounds potentiate mGluR5 activity in the presence of bound glutamate. In the absence of bound glutamate, the mGluR5 positive modulators do not demonstrate intrinsic activity. Therefore, these compounds potentiate the natural signaling of mGluR5 as opposed to agonists which activate the receptor in a permanent, unnatural manner. mGluR5 positive allosteric modulators therefore represent an approach to potentiate mGluR5 signaling which in turn potentiates and normalizes the NMDA receptor hypofunction detected in neurological and psychiatric disorders.
  • US 2005/256130 discloses aryl piperazines.
  • WO 03/051833 discloses heteroaryl substitued pyrazoles which are shown to be mGluR5 inhibitors.
    • DETAILED DESCRIPTION OF THE INVENTION
  • The present invention is directed to compounds of formula I
    Figure imgb0001
     in which
    • R1
    represents phenyl, methyl, ethyl, propyl, iso-propyl, cyclopropyl, cyclohexyl,
    Figure imgb0002
    X
    represents
    Figure imgb0003
    Figure imgb0004
    Figure imgb0005
    Figure imgb0006
    Figure imgb0007
    Figure imgb0008
    Figure imgb0009
    Figure imgb0010
    Figure imgb0011
    Figure imgb0012
    Figure imgb0013
    Figure imgb0014
    Figure imgb0015
    Figure imgb0016
    Figure imgb0017
    Figure imgb0018
    Figure imgb0019
    Figure imgb0020
    Figure imgb0021
    Figure imgb0022
    Figure imgb0023
    Figure imgb0024
    Figure imgb0025
    Figure imgb0026
    Figure imgb0027
    Figure imgb0028
    Figure imgb0029
    Figure imgb0030
    Figure imgb0031
    Figure imgb0032
    Figure imgb0033
    Figure imgb0034
    Figure imgb0035
    Figure imgb0036
    Figure imgb0037
    Figure imgb0038
    Figure imgb0039
    Figure imgb0040
    Figure imgb0041
    Figure imgb0042
    Figure imgb0043
    Figure imgb0044
    Figure imgb0045
    Figure imgb0046
    Figure imgb0047
     the group
    Figure imgb0048
     represents
    Figure imgb0049
    Figure imgb0050
    Figure imgb0051
    Figure imgb0052
    Figure imgb0053
     or a salt thereof, particularly a physiologically acceptable salt thereof. TERMS AND DEFINITIONS USED General definitions:
  • Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to.
  • In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, C1-6-alkyl means an alkyl group or radical having 1 to 6 carbon atoms. In general, for groups comprising two or more subgroups, the last named subgroup is the radical attachment point, for example, the substituent "aryl-C1-3-alkyl-" means an aryl group which is bound to a C1-3-alkyl-group, the latter of which is bound to the core or to the group to which the substituent is attached.
  • In case a compound of the present invention is depicted in form of a chemical name and as a formula in case of any discrepancy the formula shall prevail.
  • An asterisk is may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined.
  • The numeration of the atoms of a substituent starts with the atom which is closest to the core or to the group to which the substituent is attached.
  • For example, the term "3-carboxypropyl-group" represents the following substituent:
    Figure imgb0054
     wherein the carboxy group is attached to the third carbon atom of the propyl group. The terms "1-methylpropyl-", "2,2-dimethylpropyl-" or "cyclopropylmethyl-" group represent the following groups:
    Figure imgb0055
  • The asterisk may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined.
    • Stereochemistry/solvates/hydrates:
  • Unless specifically indicated, throughout the specification and the appended claims, a given chemical formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers etc...) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates including solvates of the free compounds or solvates of a salt of the compound.
    • Salts:
  • The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit/risk ratio.
  • As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. For example, such salts include salts from ammonia, L-arginine, betaine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine (2,2'-iminobis(ethanol)), diethylamine, 2-(diethylamino)-ethanol, 2-aminoethanol, ethylenediamine, N-ethyl-glucamine, hydrabamine, 1H-imidazole, lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine (2,2',2"-nitrilotris(ethanol)), tromethamine, zinc hydroxide, acetic acid, 2.2-dichloro-acetic acid, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 2,5-dihydroxybenzoic acid, 4-acetamido-benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, decanoic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, ethylenediaminetetraacetic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, D-glucoheptonic acid, D-gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycine, glycolic acid, hexanoic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, DL-lactic acid, lactobionic acid, lauric acid, lysine, maleic acid, (-)-L-malic acid, malonic acid, DL-mandelic acid, methanesulfonic acid, galactaric acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, octanoic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid (embonic acid), phosphoric acid, propionic acid, (-)-L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid. Further pharmaceutically acceptable salts can be formed with cations from metals like aluminium, calcium, lithium, magnesium, potassium, sodium, zinc and the like. (also see Pharmaceutical salts, Berge, S.M. et al., J. Pharm. Sci., (1977), 66, 1-19).
  • The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof.
  • Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention (e.g. trifluoro acetate salts,) also comprise a part of the invention.
    • Halogen:
  • The term halogen generally denotes fluorine, chlorine, bromine and iodine.
    • Alkyl:
  • The term "C1-8-alkyl", either alone or in combination with another radical denotes an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms. For example the term C1-5-alkyl embraces the radicals H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, H3C-C(CH3)2-, H3C-CH2-CH2-CH2-CH2-, H3C-CH2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-CH2-, H3C-CH2-C(CH3)2-, H3C-C(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)-and H3C-CH2-CH(CH2CH3)-.
    • Alkenyl:
  • The term "C2-n-alkenyl", is used for a group as defined in the definition for "C1-n-alkyl" with at least two carbon atoms, if at least two of those carbon atoms of said group are bonded to each other by a double bond.
    • Cycloalkyl:
  • The term "C3-7-cycloalkyl", either alone or in combination with another radical denotes a cyclic, saturated, unbranched hydrocarbon radical with 3 to n C atoms. For example the term C3-7-cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
    • Aryl:
  • The term "aryl" as used herein, either alone or in combination with another radical, denotes a carbocyclic aromatic monocyclic group containing 6 carbon atoms which may be further fused to a second 5- or 6-membered carbocyclic group which may be aromatic, saturated or unsaturated. Aryl includes, but is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl and dihydronaphthyl.
    • Heteroaryl:
  • The term "heteroaryl" means a mono- or polycyclic-ring systems containing one or more heteroatoms selected from N, O or S(O)r, wherein r=0, 1 or 2, consisting of 5 to 14 ring atoms wherein at least one of the heteroatoms is part of aromatic ring. The term "heteroaryl" is intended to include all the possible isomeric forms.
  • Thus, the term "heteroaryl" includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:
    Figure imgb0056
    Figure imgb0057
    Figure imgb0058
    Figure imgb0059
    Figure imgb0060
    Figure imgb0061
    Figure imgb0062
    Figure imgb0063
    Figure imgb0064
    Figure imgb0065
    Figure imgb0066
  • Many of the terms given above may be used repeatedly in the definition of a formula or group and in each case have one of the meanings given above, independently of one another.
    • GENERAL METHOD OF PREPARATION
  • Compounds of the present invention can be prepared in accordance with techniques that are well known to those skilled in the art.
  • Compounds of the present invention can be synthesized according to the following scheme:
    Figure imgb0067
  • Aryl ketones were deprotonated with with potassium tert butoxide and condensed with a methylesters to form a di- keton.Then, the di-keton was condensed with hydrazine to yield a pyrazole-system. The pyrazoles were coupled with 2-bromoacetic acid methyl ester under basic conditions to yield the desired pyrazol-1-yl-acetic acid methyl ester together with different quantities of the isomeric systhem. The pyrazol-1-yl-acetic acid methyl ester was hydrolyzed with LiOH to the coresponding acid. The isomeres were either seperated before ore after hydrolysis of the ester. Finally, the pyrazol-1-yl-acetic acides were coupled with an amine to the desired products.
    • Biological Assay
  • The positive modulation of mGluR5 is measured in a HEK 293 cell line expressing human recombinant mGluR5 and is detected with calcium based FLIPR assay. The cells are cultured with DMEM supplemented with 10% FCS, 2 µg/mL tetracycline, 100 µg/mL hygromycin and 500 µ/mL gneticin. The cell culture media is exchanged for tetracycline-free cell culture media 3-7 days before the assay. One day before the assay the cell culture medium is exchanged to DMEM without glutamine and phenol red and supplemented with 10% FCS, 100 µ/mL hygromycin and 500 µ/mL geneticin. On the assay day, the medium of the subconfluent cultures is removed and the cells are detached by addition of 2.5 ml EDTA(0.02%) per 175 cm2 culture flask for 1 minute. The cells are resuspend in Ringer solution (140 mM NaCl, 5 mM KCl 2.5 mM CaCl2, 1.5 mM MgCl2, 5 mM Glucose, 10 mM Hepes; adjusted to pH 7.4 with NaOH), pooled and Ringer solution added to adjust the volume to 50 mL. The cell suspension is centrifuged for 5 min at 1500U/min (425g). The supernatant is removed and the cells washed a second time with 50 ml fresh Ringer solution and centrifuged again as before. The supernatant is again removed and the pellet resuspended in Ringer solution to 1,000,000cells/ml (1x10^6 cells / mL). The cells are plated onto BD BioCoat Poly-D-Lysine 384 well plates (20.000 cells/well; 20 µl/well). The lid covered plates are then incubated until use at 37°C/10% CO2. For dye loading, 20 µl of Calcium-4 assay kit solution (prepared according to the manufacturer's description in Ringer solution) are added to the cells and the plates are incubated for 80 min 37°C and then 10 min at room temperature.
  • Controls, Compound dilution and assay execution:
    • Each assay plate contained wells with "high" and "low" controls:
      • Low controls 1%DMSO/ringer solution + basal glutamate activation (defined as 100% CTL).
      • High controls 10µM CDPPB + basal glutamate activation (defined as 200% CTL).
  • Test compounds are dissolved and diluted in DMSO to 100-fold the desired concentrations. In a second step, the compounds are diluted in Ringer solution such that the compounds are 4-fold more concentrated than the desired final assay concentration. The final DMSO concentration was 1%.
  • 20µl of each compound solution are then transferred to the assay plate and the Ca2+ kinetic is measured to determine any intrinsic compound activity. After 5 min incubation in the FLIPR device, the second stimulation with 20 µl of glutamate in Ringer solution (glutamate concentration adjusted to approximately 5% basal stimulation of the maximal possible glutamate effect) is added and the kinetic Ca2+ response of the wells was measured for the modulation effect.
    • Analysis:
  • The peak height of the Ca release related fluorescence signal (9-66) is used for the EC50. The EC50 of the modulation is calculated over a nonlinear regression with GraphPad Prism (Table 1). Table 1
    Example EC50 [nM] Example EC50 [nM] Example EC50 [nM] Example EC50 [nM]
    7.01.001 1429 7.01.080 277 7.02.061 96 7.02.139 101
    7.01.002 592 7.01.081 30 7.02.062 323 7.02.140 51
    7.01.003 1785 7.01.082 66 7.02.063 1728 7.02.141 138
    7.01.004 390 7.01.083 86 7.02.064 177 7.02.142 27
    7.01.005 381 7.01.084 34 7.02.065 194 7.02.143 48
    7.01.006 870 7.01.085 26 7.02.066 24 7.02.144 68
    7.01.007 1539 7.01.086 274 7.02.067 6 7.02.145 15
    7.01.008 1184 7.01.087 125 7.02.068 199 7.02.146 295
    7.01.009 1535 7.01.088 29 7.02.069 187 7.02.147 572
    7.01.010 695 7.01.089 22 7.02.070 40 7.02.148 15
    7.01.011 1974 7.01.090 240 7.02.071 71 7.02.149 42
    7.01.012 829 7.01.091 37 7.02.072 251 7.02.150 28
    7.01.013 617 7.01.092 33 7.02.073 627 7.02.151 211
    7.01.014 463 7.01.093 35 7.02.074 171 7.02.152 67
    7.01.015 1805 7.01.094 90 7.02.075 318 7.02.153 15
    7.01.016 143 7.01.095 53 7.02.076 293 7.02.154 108
    7.01.018 538 7.01.096 22 7.02.077 1799 7.02.155 92
    7.01.019 1661 7.01.097 109 7.02.078 232 7.02.156 170
    7.01.020 258 7.01.098 477 7.02.079 182 7.02.157 430
    7.01.021 1530 7.02.001 55 7.02.080 321 7.02.158 116
    7.01.022 511 7.02.002 1175 7.02.081 991 7.02.159 44
    7.01.023 166 7.02.003 925 7.02.082 291 7.02.160 23
    7.01.024 1157 7.02.004 689 7.02.083 35 7.02.161 35
    7.01.025 1865 7.02.005 1256 7.02.084 73 7.02.162 120
    7.01.026 503 7.02.006 1954 7.02.085 42 7.02.163 122
    7.01.027 1022 7.02.007 600 7.02.086 11 7.02.164 46
    7.01.028 1303 7.02.008 997 7.02.087 28 7.02.165 18
    7.01.029 796 7.02.009 220 7.02.088 254 7.02.166 149
    7.01.030 484 7.02.010 13 7.02.089 59 7.02.167 370
    7.01.031 1865 7.02.011 37 7.02.090 41 7.02.168 604
    7.01.032 710 7.02.012 47 7.02.091 115 7.02.169 20
    7.01.033 1531 7.02.013 92 7.02.092 369 7.02.170 30
    7.01.034 398 7.02.014 21 7.02.093 120 7.02.171 68
    7.01.035 205 7.02.015 15 7.02.094 49 7.02.172 64
    7.01.036 1322 7.02.016 110 7.02.095 6 7.02.173 38
    7.01.037 188 7.02.017 68 7.02.096 10 7.02.174 39
    7.01.038 359 7.02.018 693 7.02.097 8 7.02.175 59
    7.01.039 752 7.02.019 36 7.02.098 12 7.02.176 221
    7.01.041 1550 7.02.020 21 7.02.099 18 7.02.177 111
    7.01.042 285 7.02.021 55 7.02.100 4 7.02.178 69
    7.01.043 40 7.02.022 11 7.02.101 14 7.02.179 236
    7.01.044 1853 7.02.023 12 7.02.102 27 7.02.180 1070
    7.01.045 689 7.02.024 29 7.02.103 34 7.02.181 398
    7.01.046 1002 7.02.025 148 7.02.104 48 7.02.182 65
    7.01.047 789 7.02.026 83 7.02.105 242 7.02.183 330
    7.01.048 573 7.02.027 58 7.02.106 10 7.02.184 132
    7.01.049 652 7.02.028 943 7.02.107 39 7.02.185 258
    7.01.050 652 7.02.029 329 7.02.108 127 7.02.186 326
    7.01.051 1441 7.02.030 1761 7.02.109 61 7.02.187 1610
    7.01.052 31 7.02.031 1244 7.02.110 156 7.02.188 19
    7.01.053 914 7.02.032 37 7.02.111 334 7.02.189 15
    7.01.054 53 7.02.033 29 7.02.112 404 7.02.190 29
    7.01.055 53 7.02.034 42 7.02.113 637 7.02.191 80
    7.01.056 253 7.02.035 35 7.02.114 29 7.02.192 82
    7.01.057 740 7.02.036 136 7.02.115 8 7.02.193 290
    7.01.058 279 7.02.037 194 7.02.116 21 7.02.194 63
    7.01.059 32 7.02.038 210 7.02.117 66 7.02.195 2
    7.01.060 101 7.02.039 915 7.02.118 127 7.02.196 43
    7.01.061 163 7.02.040 1696 7.02.119 12 7.02.197 90
    7.01.062 242 7.02.041 1216 7.02.120 21 7.02.198 6
    7.01.063 334 7.02.042 192 7.02.121 49 7.02.199 16
    7.01.064 1230 7.02.043 1736 7.02.122 38 7.02.200 24
    7.01.065 173 7.02.044 735 7.02.123 71 7.02.201 171
    7.01.066 153 7.02.045 1411 7.02.124 68 7.02.202 19
    7.01.067 122 7.02.046 881 7.02.125 253 7.02.203 178
    7.01.068 236 7.02.047 221 7.02.126 68 7.02.204 47
    7.01.069 380 7.02.048 31 7.02.127 200 7.02.205 18
    7.01.070 128 7.02.049 157 7.02.128 140 7.02.206 6
    7.01.071 233 7.02.050 183 7.02.128 159 7.02.207 70
    7.01.072 245 7.02.051 190 7.02.129 156 7.02.208 36
    7.01.073 84 7.02.052 297 7.02.130 57 7.02.209 61
    7.01.074 91 7.02.053 552 7.02.131 8 7.02.210 145
    7.01.075 87 7.02.054 186 7.02.132 186 7.02.211 13
    7.01.076 412 7.02.055 42 7.02.133 276 7.02.212 3
    7.01.077 110 7.02.056 245 7.02.134 15 7.02.213 26
    7.01.078 78 7.02.057 913 7.02.135 45 7.02.214 11
    7.01.079 447 7.02.058 750 7.02.136 141 7.02.215 9
    7.02.218 54 7.02.059 287 7.02.137 352 7.02.216 6
    7.02.219 209 7.02.060 760 7.02.138 44 7.02.217 56
    7.02.220 290 7.02.231 19 7.02.242 45 7.02.253 41
    7.02.221 4 7.02.232 104 7.02.243 164 7.02.254 281
    7.02.222 23 7.02.233 280 7.02.244 48 7.02.255 7
    7.02.223 13 7.02.234 200 7.02.245 236 7.02.256 11
    7.02.224 2 7.02.235 30 7.02.246 62 7.02.257 16
    7.02.225 17 7.02.236 69 7.02.247 172 7.02.258 31
    7.02.226 11 7.02.237 111 7.02.248 290 7.02.259 10
    7.02.227 35 7.02.238 146 7.02.249 184 7.02.260 26
    7.02.228 398 7.02.239 842 7.02.250 65
    7.02.229 31 7.02.240 85 7.02.251 34
    7.02.230 878 7.02.241 76 7.02.252 69
    • MEDICAL USE
  • The present invention is directed to compounds of general formula I which are useful in the treatment of a disease and/or condition wherein the activity of an mGluR5 positive modulator is of therapeutic benefit, including but not limited to the treatment of psychotic disorders, cognitive disorders and dementias.
  • The compounds of general formula I are useful for the treatment of psychotic disorders including schizophrenia, schizoaffective disorder and substance induced psychotic disorder; cognitive disorders and dementias including age-associated learning and memory impairments or losses, post stroke dementia, deficits in concentration, mild cognitive impairment, the cognitive dysfunction in Alzheimers disease, and the cognitive dysfunction of schizophrenia.
  • Therefore, the present invention also relates to a compound of general formula I as a medicament.
  • A further aspect of the present invention relates to a compound of general formula I for the use in the treatment of a disease and/or condition wherein the activity of mGluR5 positive modulator is of therapeutic benefit.
  • Furthermore, the present invention relates to a compound of general formula I for the use in the treatment of psychotic disorders, cognitive disorders and dementias.
  • Furthermore, the present invention relates to a compound of general formula I for the use in the treatment of psychotic disorders including schizophrenia, schizoaffective disorder and substance induced psychotic disorder; cognitive disorders and dementias including age-associated learning and memory impairments or losses, post stroke dementia, deficits in concentration, mild cognitive impairment, the cognitive dysfunction in Alzheimers disease, and the cognitive dysfunction of schizophrenia.
  • The present disclosure relates to methods for the treatment or prevention of above mentioned diseases and conditions, which method comprises the administration of an effective amount of a compound of general formula I to a human being.
    • DOSAGE
  • The dose range of the compounds of general formula I applicable per day is usually from 0.1 to 5000 mg, preferably from 0.1 to 1000 mg, more preferably from 5 to 500 mg, most preferably, 10 or 100 mg. Each dosage unit may conveniently contain from 0.1 to 500 mg, preferably 10 to 100 mg.
  • The actual pharmaceutically effective amount or therapeutic dosage will of course depend on factors known by those skilled in the art such as age and weight of the patient, route of administration and severity of disease. In any case the combination will be administered at dosages and in a manner which allows a pharmaceutically effective amount to be delivered based upon patient's unique condition.
    • Pharmaceutical Compositions
  • Suitable preparations for administering the compounds of formula will be apparent to those with ordinary skill in the art and include for example tablets, pills, capsules, suppositories, lozenges, troches, solutions, syrups, elixirs, sachets, injectables, inhalatives and powders etc. The content of the pharmaceutically active compound(s) should be in the range from 1 to 99 wt.-%, preferably 10 to 90 wt.-%, more preferably 20 to 70 wt.-%, of the composition as a whole. Suitable tablets may be obtained, for example, by mixing one or more compounds according to formula I with known excipients, for example inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and/or lubricants. The tablets may also consist of several layers.
  • A further aspect of the invention is a pharmaceutical formulation including a compound of formula I in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
    • COMBINATION THERAPY
  • In another aspect the present invention relates to a combination therapy in which an active compound according to the present invention is administered together with another active compound. Accordingly, the invention also refers to pharmaceutical formulations that provide such a combination of active ingredients, whereby one of which is an active compound of the present invention. Such combinations may be fixed dose combinations (the active ingredients that are to be combined are subject of the same pharmaceutical formulation) or free dose combinations (active ingredients are in separate pharmaceutical formulations).
  • Consequently, a further aspect of the present invention refers to a combination of each of the active compounds of the present invention, preferably at least one active compound according to the present invention, with another active compound for example selected from the group of antipsychotics such as haloperidol, clozapine, risperidone, quetiapine, aripripazole, and olanzapine; antidepressants such as selective serotonin re-uptake inhibitors and dual serotonin/noradrenaline re-uptake inhibitors; mood stabilizers such as lithium valproate and lamotrigine; beta-secretase inhibitors; gamma-secretase inhibitors; gamma-secretase modulators; amyloid aggregation inhibitors such as e.g. scyllo-inositol; directly or indirectly acting neuroprotective and/or disease-modifying substances; anti-oxidants, such as e.g. vitamin E , ginko biloba or ginkolide; anti-inflammatory substances, such as e.g. Cox inhibitors, NSAIDs additionally or exclusively having Aß (Abeta) lowering properties; HMG-CoA reductase inhibitors, such as statins; acetylcholine esterase inhibitors, such as donepezil, rivastigmine, tacrine, galantamine; NMDA receptor antagonists such as e.g. memantine; AMPA receptor agonists; AMPA receptor positive modulators, AMPkines, glycine transporter 1 inhibitors; monoamine receptor reuptake inhibitors; substances modulating the concentration or release of neurotransmitters; substances inducing the secretion of growth hormone such as ibutamoren mesylate and capromorelin; CB-1 receptor antagonists or inverse agonists; antibiotics such as minocyclin or rifampicin; PDE1, PDE2, PDE4, PDE5, PDE9 or PDE10 inhibitors, GABAA receptor inverse agonists; GABAA alpha5 receptor inverse agonists; GABAA receptor antagonists; nicotinic receptor agonists or partial agonists or positive modulators; alpha4beta2 nicotinic receptor agonists or partial agonists or positive modulators; alpha7 nicotinic receptor agonists or partial agonists; histamine receptor H3 antagonists; 5-HT4 receptor agonists or partial agonists; 5-HT6 receptor antagonists; alpha2-adrenoreceptor antagonists, calcium antagonists; muscarinic receptor M1 agonists or partial agonists or positive modulators; muscarinic receptor M2 antagonists; muscarinic receptor M4 antagonists; muscarinic receptor M4 positive allosteric modulators; metabotropic glutamate receptor 5 positive allosteric modulators; metabotropic glutamate receptor 2 antagonists; metabotropic glutamate receptor 2/3 agonists; metabotropic glutamate receptor 2 positive allosteric modulators and other substances that modulate receptors or enzymes in a manner such that the efficacy and/or safety of the active compounds according to the invention is increased and/or unwanted side effects are reduced.
  • The active compounds according to the invention may also be used in combination with immunotherapies such as e.g. active immunisation with Abeta or parts thereof or passive immunisation with humanised anti-Abeta antibodies, nanobodies or antibody fragments for the treatment of the above mentioned diseases and conditions.
  • The active compounds according to the invention also may be combined with antipsychotics like haloperidol, flupentixol, fluspirilene, chlorprothixene, prothipendyl, levomepromazine, clozapine, olanzapine, quetiapine, risperidone, paliperidone, amisulpride, ziprasidone, aripiprazol, sulpiride, zotepine, sertindole, fluphenazine, perphenazine, perazine, promazine, chlorpromazine, levomepromazine, benperidol, bromperidol, pimozid, melperone, pipamperone, iloperidone, asenapine, perospirone, blonanserin, lurasidone.
  • The active compounds according to the invention also may be combined with antidepressants like amitriptyline imipramine hydrochloride, imipramine maleate, lofepramine, desipramine, doxepin, trimipramine.
    Or the active compounds according to the invention also may be combined with serotonin (5-HT) reuptake inhibitors such as alaproclate, citalopram escitalopram, clomipramine, duloxetine, femoxetine, fenfluramine, norfenfluramine, fluoxetine, fluvoxamine, indalpine, milnacipran, paroxetine, sertraline, trazodone, venlafaxine, zimelidine, bicifadine, desvenlafaxine, brasofensme and tesofensine.
  • The combinations according to the present invention may be provided simultaneously in one and the same dosage form, i.e. in form of a combination preparation, for example the two components may be incorporated in one tablet, e. g. in different layers of said tablet. The combination may be also provided separately, in form of a free combination, i.e. the active compounds of the present invention are provided in one dosage form and one or more of the above mentioned combination partners is provided in another dosage form. These two dosage forms may be equal dosage forms, for example a co-administration of two tablets, one containing a therapeutically effective amount of the active compound of the present invention and one containing a therapeutically effective amount of the above mentioned combination partner. It is also possible to combine different administration forms, if desired. Any type of suitable administration forms may be provided.
  • The active compound according to the invention, or a physiologically acceptable salt thereof, in combination with another active substance may be used simultaneously or at staggered times, but particularly close together in time. If administered simultaneously, the two active substances are given to the patient together; if administered at staggered times the two active substances are given to the patient successively within a period of less than or equal to 12, particularly less than or equal to 6 hours.
  • The dosage or administration forms are not limited, in the frame of the present invention any suitable dosage form may be used. Exemplarily the dosage forms may be selected from solid preparations such as patches, tablets, capsules, pills, pellets, dragees, powders, troches, suppositories, liquid preparations such as solutions, suspensions, emulsions, drops, syrups, elixirs, or gaseous preparations such as aerosols, sprays and the like.
  • The dosage forms are advantageously formulated in dosage units, each dosage unit being adapted to supply a single dose of each active component being present. Depending from the administration route and dosage form the ingredients are selected accordingly.
  • The dosage for the above-mentioned combination partners may be expediently 1/5 of the normally recommended lowest dose up to 1/1 of the normally recommended dose.
  • The dosage forms are administered to the patient for example 1, 2, 3, or 4 times daily depending on the nature of the formulation. In case of retarding or extended release formulations or other pharmaceutical formulations, the same may be applied differently (e.g. once weekly or monthly etc.). It is preferred that the active compounds of the invention be administered either three or fewer times, more preferably once or twice daily.
    • EXPERIMENTAL SECTION Preparation of examples for compounds of the general formula I
  • Unless otherwise stated, one or more tautomeric forms of compounds of the examples described hereinafter may be prepared in situ and/or isolated. All tautomeric forms of compounds of the examples described hereinafter should be considered to be disclosed.
  • The invention is illustrated by way of the following examples, in which the following abbreviations may be employed:
    • Abbreviations
    • RT
    room temperature
    THF
    tetrahydrofuran
    KOtBu
    Potassium tert-butanolate
    PFTU
    pentafluorphenol-tetramethyluronium hexafluorophosphat
    ACN
    acetonitrile
    MeOH
    methanol
    DIPEA
    diisopropylamine
    DEA
    diethylamine
    EtOAC
    ethyl acetate
    DMF
    dimethylformamide
    TBTU
    [(Benzotriazol-1-yloxy)-dimethylamino-methylene]-dimethyl-ammonium tetrafluoro borate
    HATU
    (O-(7-Azobenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate
    conc.
    concentrated
    min.
    minutes
    DCM
    dichlormethane
    TFA:
    trifluoro acetic acid
    LDA
    lithium diisopropylamide
    Dess-Martin
    (1, 1, 1-triacetoxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one
    DDQ
    2,3-dichlor-5,6-dicyan-p-benzochinon
    Analytical methods
  • All compounds specified in the examples below gave the correct mass spectra matching the theoretical isotope pattern. For practical reasons, only one of the major isotope peaks is given as representative data for the mass spectrum.
    • List of HPLC purification methods method 1:
  • Gilson HPLC
    • eluent:
    1. A: water with 0.10% TFA
    2. B: methanol
    gradient
  • time in min %A %B flow in ml/min
    00.00 90 10 50
    02.00 90 10 50
    11.00 0 100 50
    14.00 0 100 50
  • column: Sunfire C18, 30 x 100 mm, 10 µm (temperature: isocratic 60°C).
    • List of HPLC-analytical HPLC methods: method A:
  • Waters ZQ 2000MS, Agilent HP100, binäre pumps
    • eluent:
    1. A: water with 0.10% TFA
    2. B: methanol
    gradient:
  • time in min %A %B flow in ml/min
    0.00 95 5 1.50
    1.30 0 100 1.50
    2.50 0 100 1.50
    2.60 95 5 1.50
    • column: Sunfire C18, 4.6 x 50 mm, 3.5 µm (temperature: isocratic 40°C).
    • diodenarray detection: 210-400 nm.
    method B:
  • Waters ZQ 2000MS, Agilent HP100, binäre pumps
    • eluent:
    1. A: water with 0.10% TFA
    2. B: acetonitrile with 0.08% TFA
    gradient:
  • time in min %A %B flow in ml/min
    0.00 95 5 1.50
    2.00 0 100 1.50
    2.50 0 100 1.50
    2.60 95 5 1.50
    • column: Sunfire C18, 4.6 x 50 mm, 3.5 µm (temperature: isocratic 40°C).
    • diodenarray detection: 210-500 nm.
    method C:
  • Waters Acquity with diodenarraydetector and massdetector
    • eluent:
    1. A: water with 0.10% TFA
    2. B: methanol
    gradient
  • time in min %A %B flow in ml/min
    0.00 99 1 1.20
    0.05 99 1 1.20
    1.05 0 100 1.20
    1.25 0 100 1.20
    • column: Sunfire C18, 2.1 x 30 mm, 2,5 µm (temperature: isocratic 60°C).
    • diodenarray detektion: 210-400 nm.
    method D:
  • Waters Acquity with diodenarraydetector
    • eluent:
    1. A: water with 0.13% TFA
    2. B: methanol with 0.05% TFA
    gradient:
  • time in min %A %B flow in ml/min
    0.00 99 1 1.20
    0.05 99 1 1.20
    1.05 0 100 1.20
    1.25 0 100 1.20
    column: Sunfire C18, 2.1 x 30 mm, 2,5 µm (temperature: isocratic 60°C).
    • method E:
  • Waters Alliance with diodenarraydetector and massdetector
    • eluent:
    1. A: water with 0.10% TFA
    2. B: methanol
    gradient:
  • time in min %A %B flow in ml/min
    0.00 95 5 4.90
    1.60 0 100 4.90
    2.20 95 5 4.90
    column: Sunfire C18, 4.6 x 30 mm, 3.5 µm (temperature: isocratic 60°C).
    • method F:
  • Waters Alliance with DA and MS-detector
    • eluent:
    • A: water with 0.10% NH3
    • D: methanol
    gradient:
  • time in min %A %D flow in ml/min
    0.00 95 5 4.00
    0.20 95 5 4.00
    1.50 0 100 4.00
    1.75 0 100 4.00
    column: Waters XBridge™ C18 3.5µm, 4.6x30mm (temperature: isocratic 60°C).
    • method G:
  • Waters ZQ 2000MS, Alliance 2695
    • eluent:
    1. A: water with 0.10% TFA
    2. B: methanol
    gradient:
  • time in min %A %B flow in ml/min
    0.00 95 5 1.50
    1.30 0 100 1.50
    3.00 0 100 1.50
    3.40 95 5 1.50
    • column: Sunfire C18, 4.6 x 50 mm, 3.5 µm (temperature: isocratic 40°C).
    • diodenarray detection: 210-500 nm.
    method H:
  • Agilent 1200 System
    • eluent:
    1. A: water with 0.10% formicacid
    2. B: acetonitril 0.10% formicacid
    gradient:
  • time in min %A %B flow in ml/min
    0.00 95 5 1.60
    0.10 95 5 1.60
    1.75 5 95 1.60
    1.90 5 95 1.60
    1.95 95 5 1.60
    2.00 95 5 1.60
    • column: Zorbax StableBond C18, 3.0 x 30 mm, 1.8 µm (temperature: isocratic 25°C).
    • detection: 254 nm.
    method I:
  • Waters Acquity with diodenarraydetector and massdetector
    • eluent:
    1. A: water with 0.10% TFA
    2. B: methanol
    gradient:
  • time in min %A %B flow in ml/min
    0.00 99 1 1.30
    0.15 99 1 1.30
    1.10 0 100 1.30
    1.25 0 100 1.30
    • column: Sunfire C18, 2.1 x 30 mm, 2,5 µm (temperature: isocratic 60°C).
    • diodenarray detektion: 210-400 nm.
    method J:
  • Waters ZQ MS, Alliance 2690/2695 HPLC, Waters 996/2996 diodenarraydetector
    • eluent:
    • A: water with 0.10% TFA
    • D: methanol
    gradient:
  • time in min %A %D flow in ml/min
    0.00 95 5 4.00
    0.20 95 5 4.00
    1.60 0 100 4.00
    2.10 0 100 4.00
    • column: Waters XBridge™ C18 3.5nm, 4.6x20mm IS™ (temperature: isocratic 40°C).
    • diodenarray detection: 210-400 nm.
    method K:
  • Agilent 1200 mit DA- und MS-Detektor
    • eluent:
    1. A: water with 0.10% NH3
    2. B: methanol
    gradient:
  • time in min %A %B flow in ml/min
    0.00 95 5 2.20
    0.30 95 5 2.20
    1.50 0 100 2.20
    1.60 0 100 2.40
    1.80 0 100 2.40
    column: Xbridge C18, 3 x 30 mm, 2.5 µm (temperature: isocratic 60°C).
    • method L:
  • Waters Alliance with diodenarraydetector and massdetector
    • eluent:
    1. A: water with 0.10% TFA
    2. B: methanol with 0.10% TFA
    gradient:
  • time in min %A %B flow in ml/min
    0.00 95 5 4.00
    0.20 95 5 4.00
    1.50 0 100 4.00
    1.75 0 100 4.00
    1.85 95 5 4.00
    column: XBridge C18, 4.6 x 30 mm, 3.5 µm (temperature: isocratic 60°C).
    • method M:
  • Waters Acquity with diodenarraydetector and massdetector
    • eluent:
    1. A: water with 0.13% TFA
    2. B: methanol with 0.08% TFA
    gradient:
  • time in min %A %B flow in ml/min
    0.00 99 1 1.30
    0.05 99 1 1.30
    0.35 0 100 1.30
    0.50 0 100 1.30
    • column: Xbridge BEH C18, 2.1 x 30 mm, 1,7 µm (temperature: isocratic 60°C).
    • diodenarray detektion: 210-400 nm.
    method N:
  • Waters Alliance with DA and MS-detector
    • eluent:
    • A: water with 0.10% NH3
    • D: methanol with 0.10% NH3
    gradient:
  • time in min %A %D flow in ml/min
    0.00 95 5 4.00
    0.20 95 5 4.00
    1.50 0 100 4.00
    1.75 0 100 4.00
    column: Waters XBridge™ C18 3.5µm, 4.6x30mm (temperature: isocratic 60°C).
    • method O:
  • Waters ZMD, Alliance 2690/2695 HPLC, Waters 996/2996 diodenarraydetector
    • eluent:
    1. A: water with 0.10% TFA
    2. B: acetonitril with 0.10% TFA
    gradient:
  • time in min %A %B flow in ml/min
    0.00 95 5 2.80
    0.30 95 5 2.80
    1.60 2 98 2.80
    1.90 2 98 2.80
    2.00 95 5 2.50
    column: Merck Chromolith™ Flash RP-18e, 3 mm x 100 mm (temperature: isocratic 25°C)
    • method P:
  • Waters ZQ 2000MS, Agilent HP100, binäre pumps
    • eluent:
    1. A: water with 0.10% TFA
    2. B: methanol
    gradient:
  • time in min %A %B flow in ml/min
    0.00 80 20 2.00
    1.70 0 100 2.00
    2.50 0 100 2.00
    2.60 80 20 2.00
    • column: Sunfire C18, 4.6 x 50 mm, 3.5 µm (temperature: isocratic 60°C).
    • diodenarray detection: 210-500 nm.
    method Q:
  • Agilent 1100 with DA and MS-detector
    • eluent:
    • A: water with 0.1 % TFA
    • D: methanol
    gradient:
  • time in min %A %D flow in ml/min
    0.00 95 5 4.00
    0.15 95 5 4.00
    1.70 0 100 4.00
    2.25 0 100 4.00
    • column: Stable Bond C18 3.5µm, 4.6x30mm (temperature: isocratic 60°C).
    method R:
  • Agilent 1100 with DA and MS-detector
    • eluent:
    • A: water with 0.1 % TFA
    • D: methanol with 0.1% TFA
    gradient:
  • time in min %A %D flow in ml/min
    0.00 95 5 4.00
    0.15 95 5 4.00
    1.70 0 100 4.00
    2.25 0 100 4.00
    column: Sunfire C18 3.5µm, 4.6x30mm (temperature: isocratic 60°C).
    • method S:
  • Agilent 1200 with DA and MS-detector
    • eluent:
    • A: water with 0.2% TFA
    • D: methanol
    gradient:
  • time in min %A %D flow in ml/min
    0.00 95 5 2.20
    0.05 95 5 2.20
    1.40 0 100 2.20
    1.80 0 100 2.20
    column: Stable Bond C18, 1.8 µm, 3x30mm (temperature: isocratic 60°C).
    • method T:
  • Waters Alliance with diodenarraydetector and massdetector
    • eluent:
    1. A: water with 0.10% TFA
    2. B: methanol
    gradient:
  • time in min %A %B flow in ml/min
    0.00 95 5 4.80
    1.60 0 100 4.80
    1.85 0 100 4.80
    1.90 95 5 4.80
    column: XBridge C18, 4.6 x 30 mm, 3.5 µm (temperature: isocratic 60°C).
    • method U:
  • Waters Acquity with diodenarraydetector and massdetector
    • eluent:
    1. A: water with 0.10% TFA
    2. B: methanol
    gradient:
  • time in min %A %B flow in ml/min
    0.00 99 1 1.40
    0.05 99 1 1.40
    1.00 0 100 1.40
    1.25 0 100 1.40
    • column: Xbridge C18, 2.1 x 20 mm, 2,5 µm (temperature: isocratic 60°C).
    • diodenarray detektion: 210-400 nm.
    method V:
  • Agilent 1200 with DA and MS-detector
    • eluent:
    • A: water with 0.2% TFA
    • D: methanol
    gradient:
  • time in min %A %D flow in ml/min
    0.00 95 5 2.20
    0.05 95 5 2.20
    1.40 0 100 2.20
    1.80 0 100 2.20
    column: Sunfire C18, 2.5 µm, 3x30mm (temperature: isocratic 60°C).
    • method W:
  • Waters Alliance with diodenarraydetector and massdetector
    • eluent:
    1. A: water with 0.10% TFA
    2. B: methanol
    gradient:
  • time in min %A %B flow in ml/min
    0.00 95 5 4.00
    1.60 0 100 4.00
    1.85 0 100 4.00
    1.90 95 5 4.00
    column: XBridge C18, 4.6 x 30 mm, 3.5 µm (temperature: isocratic 60°C).
    • method X:
  • Waters Acquity with diodenarraydetector and massdetector
    • eluent:
    1. A: water with 0.13% TFA
    2. B: methanol with 0.05% TFA
    gradient:
  • time in min %A %B flow in ml/min
    0.00 99 1 1.30
    0.05 99 1 1.30
    0.35 0 100 1.30
    0.50 0 100 1.30
    • column: Xbridge BEH C18, 2.1 x 30 mm, 1,7 µm (temperature: isocratic 60°C).
    • diodenarray detektion: 210-400 nm.
    method Y:
  • Waters Alliance with diodenarraydetector and massdetector
    • eluent:
    1. A: water with 0.10% TFA
    2. B: methanol
    gradient:
  • time in min %A %B flow in ml/min
    0.00 95 5 4.00
    1.60 0 100 4.00
    1.85 95 5 4.00
    1.90 95 5 4.00
    column: Sunfire C18, 4.6 x 30 mm, 3.5 µm (temperature: isocratic 60°C).
    • method Z:
  • Waters Acquity with diodenarraydetector and massdetector
    • eluent:
    1. A: water with 0.1 % TFA
    2. B: methanol
    gradient
  • time in min %A %B flow in ml/min
    0.00 99 1 1.50
    0.05 99 1 1.50
    1.05 0 100 1.50
    1.20 0 100 1.50
    column: Xbridge BEH Phenyl, 2.1 x 30 mm, 1.7 µm (temperature: isocratic 60°C)
    • method AA:
  • Waters Acquity with diodenarraydetector and massdetector
    • eluent:
    1. A: water with 0.1 % TFA
    2. B: methanol
    gradient
  • time in min %A %B flow in ml/min
    0.00 99 1 1.50
    0.05 99 1 1.50
    1.00 0 100 1.50
    1.10 0 100 1.50
    column: Xbridge Phenyl, 2.1 x 20 mm, 2.5 µm (temperature: isocratic 60°C)
    • method AB:
  • Waters Alliance with DA and MS-detector
    • eluent:
    • A: water with 0.10% NH3
    • D: methanol with 0.10% NH3
    gradient:
  • time in min %A %D flow in ml/min
    0.00 95 5 4.00
    0.20 95 5 4.00
    1.50 0 100 4.00
    1.75 0 100 4.00
    column: Waters XBridge™ C18 3.5µm, 4.6x30mm (temperature: isocratic 60°C).
    • method AC:
  • Waters Alliance with diodenarraydetector and massdetector
    • eluent:
    1. A: water with 0.10% NH3
    2. B: methanol
    gradient:
  • time in min %A %B flow in ml/min
    0.00 95 5 4.00
    0.20 95 5 4.00
    1.50 0 100 4.00
    1.75 0 100 4.00
    column: XBridge C18, 4.6 x 30 mm, 3.5 µm (temperature: isocratic 60°C).
    • method AD:
  • Waters SQD MS, Aquility UPLC, diodenarray: 210-500 nm
    • eluent:
    1. A: water with 0.10% TFA
    2. B: acetonitrile with 0.08% TFA
    gradient:
  • time in min %A %B flow in ml/min
    0.00 95 5 1.50
    0.70 0 100 1.50
    0.70 0 100 1.50
    0.81 95 5 1.50
    1.90 0 100 0.20
    column: Ascentis Express C18, 2.1 x 50 mm, 2.7 µm (temperature: isocratic 60°C).
    • method AE:
    • Applied Biosystem: LCM/MS API 2000, HPLC: Shimadzu Prominence
    • dual wavelength: 220 and 260 nm
    eluent:
    1. A: water with 0.05% TFA
    2. B: acetonitrile
    gradient:
  • time in min %A %B flow in ml/min
    0.01 90 10 1.20
    1.50 70 30 1.20
    3.00 10 90 1.20
    4.00 10 90 1.20
    5.00 90 10 1.20
    column: Gemini C18, 4.6 x 50 mm, 2.7 µm (temperature: isocratic 20°C).
    • method AF:
  • Agilent 1200 with DA and MS-detector
    • eluent:
    1. A: water with 0.2% TFA
    2. B: methanol
    gradient:
  • time in min %A %B flow in ml/min
    0.00 95 5 1.80
    0.05 95 5 1.80
    1.70 0 100 1.80
    1.75 0 100 2.50
    column: Sunfire C18, 2.5 µm, 3x30mm (temperature: isocratic 60°C).
    • method AG: eluent:
    1. A: acetonitril 95% and water 5% with 0.1% TFA
    2. B: water 95% and acetonitril 5% with 0.1% TFA
    gradient:
  • time in min %A %B flow in ml/min
    00.00 20 80
    15.00 80 20
    20.00 80 20
    column: Zorbax 300 SB-C8 (Agilent) 3,5µm; 4,6 x 150mm (temperature: isocratic 60°C).
    • method AH:
  • Waters ZQ 2000MS, Agilent HP100, binäre pumps
    • eluent:
    1. A: water with 0.10% TFA
    2. B: methanol
    gradient:
  • time in min %A %B flow in ml/min
    0.00 95 5 1.50
    1.30 0 100 1.50
    2.50 0 100 1.50
    2.60 95 5 1.50
    • column: Sunfire C18, 4.6 x 50 mm, 3.5 µm (temperature: isocratic 60°C).
    • diodenarray detection: 210-500 nm.
    Synthesis of intermediates 6.01. Synthesis of building blocks 6.01.01 5, 6, 7, 8-Tetrahydro-4H-thiazolo-[4, 5-d]-azepin-2-ylamine hydrobromide
  • Figure imgb0068
    • 6.01.01.1 5-Bromo-azepan-4-one hydrobromide
  • Figure imgb0069
  • 32 mL 62% HBr solution in 50 mL conc. acetic acid was added to 50 g hexahydro-azepin-4-on hydrochloride in 600 mL conc. acetic acid. Then 17.2 mL bromine in 50 mL conc. acetic acid was dropped to the reaction. The solvent was removed and the residue was crystallized from a mixture of DCM/ MeOH (8/2) to give 79 g of the desired compound. (M+H)+: 192
    • 6.01.01.2 5, 6, 7, 8-Tetrahydro-4H-thiazolo-[4, 5-d]-azepin-2-ylamine hydrobromide
  • Figure imgb0070
  • 1.44 g thiourea was added to 4 g 5-bromo-azepan-4-one hydrobromide in 50 mL ethanol and stirred 3h at 80°C and over the weekend at RT. The precipitate was filltered and dried to yield 3.8 g of the product.
    Rt: 0.61 min (method F)
    (M+H)+: 170
  • By using the same synthesis strategy as for 5, 6, 7, 8-Tetrahydro-4H-thiazolo-[4, 5-d]-azepin-2-ylamine hydrobromide the following compounds were obtained:
    Examples Product MS m/z [M+H]+ HPLC Method Rt min
    6.01.02
    Figure imgb0071
         		169 Method H 0.33
    6.01.03
    Figure imgb0072
         		184 Method N 0.69
    • 6.01.04.01 4-Chloro-6-methoxy-pyrimidine
  • Figure imgb0073
  • 3.1 g sodiummethanolate was added to 7.2 g 4, 6-dichlorpyrimidine in 150 mL methanol at 0°C. The reaction was warmed to RT and stirred additional 3h. Water and EtOAC were added and the layers were seperated. The organic layer was dried and evaporated to give 7.1 g of the desired product.
    Rt: 0.85 min (method L), (M+H)+: 144
    • 6.01.12.01 4-Hydroxy-4-pyrimidin-2-yl-piperidine-1-carboxylic acid tert-butyl ester
  • Figure imgb0074
  • 9.9 mL 1.6 mol/L n-buthyllithium solution in hexane was added to 3.85 g 2-tributylstannanyl-pyrimidine at -78°C. The reaction was stirred 30 min. at -78°C and 2.1 g 1- carboxylic acid tert-butyl ester-4-piperidone in 10 mL THF was added. The reaction was warmed up and stirred over night at RT. Then, the reaction was cooled to 0°C and water was added slowly. EtOAC was added and the layers were seperated. The organic layer was washed one time with water and two times with a saturated ammonia chloride solution. Then, the organic layer was dried and evaporated. The residue was purified by HPLC to yield 448 mg.
    Rt: 1.21 min (method J), (M+H)+: 133/162/180
    • 6.01.04.02 4-(6-Methoxy-pyrimidin-4-yl)-3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester
  • Figure imgb0075
  • 0.5 g tetrakis (triphenylphosphine) palladium was added to 1.3 g 4-chloro-6-methoxy-pyrimidine and 4-(4, 4, 5, 5-tetramethyl-(1, 3, 2) dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester) and 9 mL 2 mol/L sodiumcarbonate in 40 mL dioxane. The reaction was stirred 15 min. under microwave conditions. Water was added and the reaction was extracted with DCM. The organic layer was dried and evaporated. The residue was purified by HPLC to give 1.44g of the desired product.
    Rt: 1.38 min (method L)
    (M+H)+: 292
  • By using the same synthesis strategy as for 4-(6-methoxy-pyrimidin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester the following compound was obtained:
    Examples Product MS m/z [M+H]+ HPLC Method Rt min
    6.01.05.02
    Figure imgb0076
         		163//205/261 method J 1.02
    6.01.06.02
    Figure imgb0077
         		292 method I 0.96
    6.01.07.02
    Figure imgb0078
         		276 method I 0.82
    6.01.08.02
    Figure imgb0079
         		280 method I 0.92
    6.01.09.02
    Figure imgb0080
         		276
    6.01.10.02
    Figure imgb0081
         		266 method I 0.86
    6.01.11.02
    Figure imgb0082
         		281 method I 0.90
    • 6.01.12.02 4-Pyrimidin-2-yl-3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester
  • Figure imgb0083
  • 110 mg 4-hydroxy-4-pyrimidin-2-yl-piperidine-1-carboxylic acid tert-butyl ester was dissolved in 2.5 mL pyridine and 0.18 ml phosphoroxychloride was added. The reaction was stirred one day at RT. The reaction was decomposed with water and extracted with DCM. The organic layer was dried and the solvent was removed to give 84 mg of the desired compound.
    Rt: 1.33 min (method J)
    (M+H)+: 162/206/262
    • 6.01.04.03 4-(6-Methoxy-pyrimidin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester
  • Figure imgb0084
  • 150 mg palladium charcoal was added to 765 mg 4-(6-methoxy-pyrimidin-4-yl)-3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester in 90 mL methanol. The reaction was stirred 3.5 h at RT and 3 bar hydrogen. Then, the reaction was filltered and evaporated to give 769 mg of the desired product.
    Rt: 1.31 min (method J)
    (M+H)+: 194/238/294
  • By using the same synthesis strategy as for 4-(6-methoxy-pyrimidin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester the following compound was obtained:
    Examples Product MS m/z [M+H]+ HPLC Method Rt min
    6.01.05.03
    Figure imgb0085
         		263//207/163 method J 1.04
    6.01.06.03
    Figure imgb0086
         		294 method I 0.91
    6.01.11.03
    Figure imgb0087
         		283 method I 0.86
    • 6.01.04 4-Methoxy-6-piperidin-4-yl-pyrimidine
  • Figure imgb0088
  • 1.16 g 4-(6-Methoxy-pyrimidin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester were stirred in 2 mL 4 mol/L HCl solution in dioxane for 40 min. The mixture was diluted with dioxane and basified with sodiumcarbonate. The suspension was filtered and the filtrate was concentrated to give 0.24 g of the desired product.
    Rt: 1.31 min (method L)
    (M+H)+: 194/238/294
  • By using the same synthesis strategy as for 1', 2', 3', 4', 5', 6'-hexahydro-(2,4') bipyridinyl hydrochlorid the following compounds were obtained:
    Examples Product MS m/z [M+H] + HPLC Method Rt min
    6.01.05
    Figure imgb0089
         		263/207/163 method J 1.04
    6.01.06
    Figure imgb0090
         		194 method I 0.45
    6.01.07
    Figure imgb0091
         		176 method F 0.87
    6.01.08
    Figure imgb0092
         		180 method F 0.96
    6.01.09
    Figure imgb0093
         		176 method F 0.95
    6.01.10
    Figure imgb0094
         		166 method F 0.44
    6.01.11
    Figure imgb0095
         		183 method I 0.35
    6.01.15
    Figure imgb0096
         		181 method I 0.52
    • 6.01.16.01 3-Bromo-piperidin-4-one hydrobromide
  • Figure imgb0097
  • 4.7 mL 33% HBr in acetic acid, 11.4 g bromine in 30 mL acetic acid was added slowly to a stirred solution of 10 g piperidine-4,4-diol in 60 mL acetic acid at RT. The reaction mixture was stirred additional 45 min at ambient temperature and the acetic acid was completely removed under reduced pressure. The residue was dissolved in 200 mL acetone and refluxed for 1 hour, cooled, filtered and washed with acetone and dried to give 15.2 g of the desired product (M+H)+: 180.
    • 6.01.16.02 4, 5, 6, 7-Tetrahydro-thiazolo (5, 4-c) pyridin-2-ylamine dihydrobromide
  • Figure imgb0098
  • 4.55 g thiourea was added to 15.2 g 3-Bromo-piperidin-4-one hydrobromide in 152 mL ethanol and refluxed for 20h. The reaction was cooled and the solid was filtered, washed with ethanol and dried to give 15.8 g of the desired product.
    (M+H)+: 184
    • 6.01.16.03 2-Amino-6, 7-dihydro-4H-thiazolo (5, 4-c) pyridine-5-carboxylic acid tert-butyl ester
  • Figure imgb0099
  • 15.8 g 4, 5, 6, 7-tetrahydro-thiazolo (5, 4-c) pyridin-2-ylamine and 100 mL dioxane was added to 15.2 g potassium carbonate in 158 mL water. 13.1 g di tert-butyl dicarbonate in 58 mL dioxane was added at 0°C. The reaction mixture was allowed to stir for 3h at ambient temperature. The reaction mixture was diluted with water and the solid was filtered through silica gel, washed with water (2 x 50 mL) to afford the desired product. The filtrate was concentrated, diluted with water and extracted with ethyl acetat. The organic layer was dried over magnesium sulfate and concentrated to afford 11.6 g desired product.
    1H NMR (400 MHz, DMSO-d6): δ 1.41 (s, 9H), 2.43 (t, 2H), 3,56 (t, 2H), 4.28 (s, 2H), 6.80 (s, 2H)
    (M+H)+: 256
  • By using the same synthesis strategy as for 2-amino-6, 7-dihydro-4H-thiazolo (5, 4-c) pyridine-5-carboxylic acid tert-butyl ester the following compound was obtained:
    Examples Product MS m/z [M+H]+ HPLC Method Rt min
    6.01.17.01
    Figure imgb0100
         		270
    • 6.01.16.04 2-Phenoxycarbonylamino-6, 7-dihydro-4H-thiazolo (5, 4-c) pyridine-5-carboxylic acid tert-butyl ester
  • Figure imgb0101
  • 39 g calcium carbonate and 36.8 g phenyl chloroformate in 250 mL THF was added to a stirred solution of 50 g 2-amino-6, 7-dihydro-4H-thiazolo (5, 4-c)pyridine-5-carboxylic acid tert-butyl ester in 1L THF. The reaction mixture was allowed to stir for 15h. The reaction mixture was filtered through silica gel and the filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate and the organic layer was dried over magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was washed with 20% ethyl acetate in hexane to give 60 g of the desired product.
    1H NMR (400 MHz, CDCl3): δ 1.44 (s, 9H), 2.81 (s, 2H), 3.66 (s, 2H), 4.53 (s, 2H), 7.18 (d, 2H), 7.25 - 7.30 (m, 1H), 7.41 (t, 2H), 11.99 (br s, 1H)
    (M+H)+: 376
    • 6.01.16.05 2-(3-allyl-ureido)-6, 7-dihydro-4H-thiazolo (5, 4-c) pyridine-5-carboxylic acid tert-butyl ester
  • Figure imgb0102
  • 45 mg allylamin was added to 200 mg 2-phenoxycarbonylamino-6, 7-dihydro-4H-thiazolo (5, 4-c) pyridine-5-carboxylic acid tert-butyl ester in 25 mL DMF. The reaction was stirred for 12h at RT, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine solution and concentrated. The residue was purified by column chromatographie (silica gel, eluent: 40% ethylacetate in hexane) to give 179 mg of desired product. (M+H)+: 339
    • 6.01.16 1-allyl-3-(4, 5, 6, 7-tetrahydro-thiazolo (5, 4-c) pyridin-2-yl)-urea
  • Figure imgb0103
  • 10 % TFA in 60 ml chloroform was added to 2.5 g 2-(3-allyl-ureido)-6, 7-dihydro-4H-thiazolo (5, 4-c) pyridine-5-carboxylic acid tert-butyl ester in 28 ml chloroform and stirred for 2 h at RT. The mixture was concentrated, the residue was diluted with chloroform and basified with 2.5 M aqueous potassium carbonate solution and extracted wih chloroform. The organic layer was concentrated. The residue was washed with a mixture 50% ethyl acetate and 50% hexane to yield 1.7 g of the desired product. (M+H)+: 239
    • 6.01.17.02 2-acetylamino-4, 5, 7, 8-tetrahydro-thiazolo (4,5-d) azepine-6-carboxylic acid tert-butyl ester
  • Figure imgb0104
  • 95 mg acetyl chloride was added to 312 mg 2-Amino-4, 5, 7, 8-tetrahydro-thiazolo (4, 5-d) azepine-6-carboxylic acid tert-butyl ester in 5 mL pyridine at 15°C. The reaction was stirred 3h at RT. The reaction was diluted with dichlormethane and 1mL water was added. The solution was filtered over 40 mL Alox and 100 mL Extrelut and evaporated to give 127 mg desired product. (M+H)+: 312
  • By using the same synthesis strategy as for 1-allyl-3-(4, 5, 6, 7-tetrahydro-thiazolo (5, 4-c) pyridin-2-yl)-urea the following compounds were obtained:
    Examples Product MS m/z [M+H]+ HPLC Method Rt min
    6.01.17
    Figure imgb0105
         		212
    • 6.01.18 4-(5-Isopropyl-(1, 3, 4) oxadiazol-2-yl)-4-methyl-piperidine
  • Figure imgb0106
    • 6.01.18.01 4-methyl-piperidine-1, 4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester
  • Figure imgb0107
  • 137 mL Diisopropylamine in 3390 mL THF was cooled to 0°C and 360 mL n-buthyllithium was added dropwise under nitrogen. The reaction was cooled to -78°C and a solution of 180 mL piperidine-1, 4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester in 1800 mL THF was added dropwise over 1h. The reaction was stirred at -78°C for 2h and then 168 mL methyliodide in 300 mL THF was added in one portion. The mixture was stirred 2h at -78°C and then allowed to warm to RT. The reaction was quenched with saturated aqueous sodium sulfate solution, the organig phase was seperated, dried and evaporated. The residue was purified by chromatography on silica gel to give 155 g of the desired product.
    Rf: 0.3 (petrolether/EtOAC= 10/1)
    1H NMR (TH03330-021-1, 400 MHz, CDCl3): δ3.67-3.65 (m, 2H, CH2), 3.62 (s, 3H, CH3), 2.93-2.87 (m, 2H, CH2), 2.00-1.95 (m, 2H, CH2), 1.37 (s, 9H, 3CH3), 1.31-1.25 (m, 2H, CH2), 1.12 (s, 3H, CH3).
    • 6.0.1.18.02 4-hydrazinocarbonyl-4-methyl-piperidine-1-carboxylic acid tert-butyl ester
  • Figure imgb0108
  • 100 g 4-methyl-piperidine-1, 4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester was dissolved in 100 mL methanol and 300 mL hydrazine monohydrate was added. The mixture was reflux overnight. The reaction was cooled to RT and then concentrated to dryness under vacuum to give compound 89 g desired product.
    Rf: 0.2 (DCM/ MeOH= 20/1)
  • By using the same synthesis strategy as for 4-hydrazinocarbonyl-4-methyl-piperidine-1-carboxylic acid tert-butyl ester the following compound was obtained:
    Examples Product NMR Rf
    6.01.19.02
    Figure imgb0109
         		1NMR: (400 MHz, MeOD): δ 4.08 (d, J = 13.2 Hz, 2H, CH2), 2.27 (br, 2H, NH2), 2.38-2.29 (m, 1H, CH), 1.72-1.68 (m, 2H, CH2), 1.63-1.56 (m, 2H, CH2), 1.45 (s, 9H, 3CH3). 0.2 (DCM/ MeOH= 20/1)
    • 6.01.18.03 4-(5-isopropyl-(1, 3, 4) oxadiazol-2-yl)-4-methyl-piperidine-1-carboxylic acid tert-butyl ester
  • Figure imgb0110
  • 30 g 4-hydrazinocarbonyl-4-methyl-piperidine-1-carboxylic acid tert-butyl ester was refluxed with 150 mL 1, 1, 1-trimethoxy-2-methyl-propane overnight. The excess of reagent was removed under vaccuum and the residue was purified by chromatography on silica gel to give 19 g of the desired product.
    1H NMR (TH03330-027-1, 400 MHz, CDCl3): δ 3.76-3.75 (m, 2H, CH2), 3.31-3.30 (m, 1H, CH), 3.22-3.17 (m, 2H, CH2), 2.18-2.15 (m, 2H, CH2), 1.68-1.62 (m, 2H, CH2), 1.45-1.38 (m, 9H, BocH), 1.37 (s, 9H, CH3).
  • By using the same synthesis strategy as for 4-(5-isopropyl-(1, 3, 4) oxadiazol-2-yl)-4-methyl-piperidine-1-carboxylic acid tert-butyl ester the following compound was obtained:
    Examples Product NMR Rf
    6.01.19.03
    Figure imgb0111
         		1H-NMR (400 MHz, MeOD): δ 4.08-4.04 (m, 2H, CH2), 3.20-3.13 (m, 2H, 2CH), 3.01 (br, 2H, CH2), 2.07-2.03 (m, 2H, CH2), 1.75-1.68 (m, 2H, CH2), 1.46 (s, 9H, 3CH3), 1.36 (d, J = 6.8 Hz, 6H, 2CH3). 0.3 (DCM/ MeOH= 20/1)
    • 6.01.18 4-(5-Isopropyl-(1, 3, 4) oxadiazol-2-yl)-4-methyl-piperidine
  • Figure imgb0112
  • 150 mL saturated dioxane-HCl was added to 19 g 4-(5-isopropyl-(1, 3, 4) oxadiazol-2-yl)-4-methyl-piperidine-1-carboxylic acid tert-butyl ester in 100 mL dioxane at 0°C. The mixture was stirred at RT for 2 h. The precipitate was filtered and washed with ethyl acetate to give 15.1 g of the desired product.
    1H NMR (TH03335-030-4, 400 MHz, MeOD): δ 3.38-3.33 (m, 2H, CH2), 3.22-3.16 (m, 1H, CH), 3.13-3.10 (m, 2H, CH2), 2.44-2.39 (m, 2H, CH2), 2.03-1.95 (m, 2H, CH2), 1.46 (s, 3H, CH3), 1.38 (d, J = 7.2 Hz, 6H, 2CH3).
  • By using the same synthesis strategy as for 4-(5-isopropyl-(1, 3, 4) oxadiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester the following compound was obtained:
    Examples Product MS m/z [M+H]+
    6.01.19
    Figure imgb0113
         		1H-NMR (400 MHz, MeOD): δ 3.49-3.44 (m, 2H, CH2), 3.38-3.34 (m, 1H, CH), 3.22-3.16 (m, 3H, CH2/CH), 2.36-2.32 (m, 2H, CH2), 2.09-2.02 (m, 2H, CH2), 1.37 (d, J = 7.2 Hz, 6H, CH3).
    • 6.01.20.01 2-methylamino-4, 5, 7, 8-tetrahydro-thiazolo (4, 5-d) azepine-6-carboxylic acid tert-butyl ester
  • Figure imgb0114
  • 104 mg 60% sodium hydrid was added to 700 mg 2-amino-4, 5, 7, 8-tetrahydro-thiazolo (4, 5-d) azepine-6-carboxylic acid tert-butyl ester in 1.5 mL THF at 0°C. Then, 162 µL methyliodide was dropped to the mixture. The reaction was stirred over night at RT. The solvent was removed and the residue was purified by HPLC and 121 mg of the desired product was obtained. (M+H)+: 284
    • 6.01.21 4-phenyl-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-d]azepine hydrochloride
  • Figure imgb0115
    • 6.01.21.01 (1-benzyl-5-chloro-2, 3, 6, 7-tetrahydro-1H-azepin-4-yl)-phenyl-methanol
  • Figure imgb0116
  • 136.6 g brombenzol in 300 mL diethylether was added to 21.2 g magnesium in 100 mL diethylether. The Grignard reaction is initiated with a small amount of iodine, kept at reflux by adding the bromebenzole and stirred additional 15 min for compleation. Then, 21.2 g 1-benzyl-5-chloro-2, 3, 6, 7-tetrahydro-1H-azepine-4-carbaldehyde in 300 mL diethylether was added. The mixture was stirred 2h in a warm water bath and quenched with 200 ml 6 M HCl solution at 0°C. The reaction was filtered and the filtrate was washed wih diethylether and water. The filtrate was disolved in sodium carbonate solution and chloroform. The layers were seperated and the organic layer was washed with water and evaporated to give 89.9 g of the desired product. Fp:124°C
    • 6.01.21.02 (1-benzyl-5-chloro-2, 3, 6, 7-tetrahydro-1H-azepin-4-yl)-phenyl-methanone
  • Figure imgb0117
  • 89 g (1-benzyl-5-chloro-2, 3, 6, 7-tetrahydro-1H-azepin-4-yl)-phenyl-methanol in 800 mL dichlormethane was dropped to 115.4 g pyridiniumchlorchromate in 600 mL dichlormethane. The reaction was stirred 2.5 days at RT. Potassiumcarbonate-solution was added to the reaction. The mixture was stirred 2h at RT and filtered over celite. The layers were seperated and the organic layer was washed with water. The solvent was removed and the residue was purified by chromatography on silica gel (toluol/EE: 8.5:1.5). The solvent was removed and 64.6 g of the desired compound was obtained. Rf: 0.5 (toluol/EE: 8.5:1.5)
    • 6.01.21.03 7-benzyl-4-phenyl-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-d]azepine
  • Figure imgb0118
  • 16.8 g sodium was added to 500 mL ethanol at 10°C. Then, 48.5 g formamidine hydrochloride was added and the reaction was stirred 15 min at 6°C. 28 g (1-benzyl-5-chloro-2, 3, 6, 7-tetrahydro-1H-azepin-4-yl)-phenyl-methanone was added and the reaction was stirred 17.5 h at RT and 1h at 40°C. The mixture was filtered and the solvent was removed. The residue was dissolved in ethyl acetate. The layers were seperated and the organic layer was washed with water and evaporated. The residue was crystalysed with diethylether to yield 10.7 g of the desired product. Fp: 81-82°C
    • 6.01.21.04 4-phenyl-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-d]azepine hydrochloride
  • Figure imgb0119
  • Palladium charcoal was added to 17 g 7-benzyl-4-phenyl-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-d] azepine in 250 mL ethanol and 54 mL 1 mol/L HCl solution. The reaction was stirred at 80°C and 5 bar hydrogen. The mixture was filltered and evaporated to give 13.15 g of the desired product.
    • 6.01.22 4-(5-Methyl-oxazol-2-yl)-piperidine
  • Figure imgb0120
    • 6.01.22.01 N-(2-Hydroxy-propyl)-isonicotinamide
  • Figure imgb0121
  • 289 g 1-amino-propan-2-ol was added to 75 g isonicotinoyl chloride and 549 mL triethylamine in 2 L anhydrous dichlormethane at 0°C under nitrogen atmosphere. After 30 min at 0 °C the reaction was concentrated under vacuum and the residue was re-suspended in 5 L ethyl acetate. The precipitate was removed by filtration. The filtrate was concentrate and recrystallized from ethyl acetate to give 154 g of the desired product.
    Rf: 0.4 (dichlormethane:20/methanol:1)
    (M+H)+: 181
    • 6.01.22.02 N-(2-Oxo-propyl)-isonicotinamide
  • Figure imgb0122
  • A solution of 154 g N-(2-hydroxy-propyl)-isonicotinamide in 800 mL dichlormethane was added dropwise to a solution of 438 g Dess-Martin reagent in 1.2 L dichlormethane at 0 °C under nitrogen atmosphere. After 30 min at 0 °C, the solution was stirred at RT for 4 h. The mixture was concentrated under vacuum and the resulting crude product was purified by flash chromatography (silica gel) to give 91 g of the desired product.
    Rf: 0.55 (dichlormethane/methanol:20/1), (M+H)+: 179
    • 6.01.22.03 4-(5-Methyl-oxazol-2-yl)-piperidine
  • Figure imgb0123
  • 20 g N-(2-oxo-propyl)-isonicotinamide was dissolved in 200 mL phosphoroxychloride at 0°C and the mixture was heated to 120 °C overnight. The reaction was quenched with cold water and then extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated under vacuum. The resulting crude product was purified by flash chromatography (silica gel) to give compound 10.5 g of the desired product.
    Rf: 0.35 (petrolether/ethyl acetate:1/1), (M+H)+: 167
    • 6.01.23 4-(5-Methyl-oxazol-2-yl)-1, 2, 3, 6-tetrahydro-pyridine hydrochloride
  • Figure imgb0124
    • 6.01.23.01 1-Benzyl-4-(5-methyl-oxazol-2-yl)-pyridinium
  • Figure imgb0125
     141 g benzylbromide was added to 66 g 4-(5-methyl-oxazol-2-yl)-piperidine at RT and the mixture was heated at reflux overnight. The precipitate was collected by filtration and washed with acetone, dried under vacuum to give compound 126 g desired product.
    Rf: 0.00 (petrolether/ethyl acetate:1/1), (M+H)+: 252
    • 6.01.23.02 1-Benzyl-4-(5-methyl-oxazol-2-yl)-1, 2, 3, 6-tetrahydro-pyridine
  • Figure imgb0126
  • 21.6 g sodium borohydride was added to 130 g 1-benzyl-4-(5-methyl-oxazol-2-yl)-pyridinium in 1.5 L ethanol at 0 °C under nitrogen atmosphere. After 30 min at 0 °C, the solution was stirred at RT for 2 h. The mixture was concentrated and treated with water and ethyl acetate. The organic layers were separated and aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under vacuum. The resulting crude product was purified by flash chromatography (silica gel) to give 81.2 g of the desired product. Rf: 0.3 (petrolether/ethyl acetate:1/1), (M+H)+: 255
    • 6.01.23.03 4-(5-Methyl-oxazol-2-yl)-1, 2, 3, 6-tetrahydro-pyridine hydrochloride
  • Figure imgb0127
  • 20 g 1-chloroethyl chloroformate was added to 24 g 1-benzyl-4-(5-methyl-oxazol-2-yl)-1, 2, 3, 6-tetrahydro-pyridine in 200 mL anhydrous dichlormethane at 0 °C under nitrogen atmosphere. After 2 h, the solution was concentrated and 200 mL anhydrous methanol was added. The mixture was heated at reflux for 4 h and concentrated. The resulting crude product was recrystallized from dichlormethane to give 16 g of the desired product.
    Rf 0.0 (petrolether/ethyl acetate:1/1)
    (M+H)+: 165
    • 6.01.24 5, 6-Dimethyl-pyridine-2-carboxylic acid methyl ester
  • Figure imgb0128
  • 77.4 ml 2 mol/L trimethylsilyldiazomethan in hexane was added to 5, 6-dimethyl-pyridine-2-carboxylic acid in 150 mL methanol and 600 mL dichlormethane at -5 °C and the reaction was stirred for 0.5h. After warming to RT the solvent was removed and the residue was purified by chromatorgaphie on Silica (cyclohexane/ethyl acetate: 7/ 3) to give 12.8 g of the desired product. Rt: 0.49 (method M), (M+H)+: 166
    • 6.01.25 2-Methyl-isonicotinic acid methyl ester
  • Figure imgb0129
  • 5 g 2-methyl-isonicotinic acid was stirred 24 h at 50°C in 150 mL 1.3 mol/L HCl in methanol. The solvent was removed and water was added to the residue. The mixture was basified with saturated sodiumhydrogencarbonate solution and extracted with ethylacetate. The organic layer was dried with magnesiumsulfate and evaporated to give 4.5 g of the desired product.
    Rt: 0.36 (method S), (M+H)+: 152
    • 6.01.26 1-(5-Methyl-(1, 2, 4) oxadiazol-3-yl)-piperazine hydrochloride
  • Figure imgb0130
    • 6.01.26.01 4-Cyano-piperazine-1-carboxylic acid tert-butyl ester
  • Figure imgb0131
     3.76 g bromcyane was added to 6 g piperazine-1-carboxylic acid tert-butyl ester and 6.3 mL DIPEA in 30 mL dichlormethane at 0 °C. The reaction was stirred 1.5 h at 0 °C. Water and dichlormethane was added and the layers were seperated. The organic layer was washed with brine and water and evaporated to give 6.8 g of the desired product.
    Rt: 1.13 (method AB), (M+H-56)+: 156
    • 6.01.26.02 4-(5-Methyl-(1, 2, 4)-oxadiazol-3-yl)-piperazine-1-carboxylic acid tert-butyl ester
  • Figure imgb0132
  • 5.3 mL triethylamine and 2.6 g hydroxylamine hydrochloride were added to 6.8 g 4-cyano-piperazine-1-carboxylic acid tert-butyl ester in 50 mL ethanol. The reaction was stirred 2h at 80 °C. The solvent was removed and 50 mL pyridine and 3.7 mL acetic anhydride were added to the residue and stirred at 80 °C over night. The mixture was evaporated. Water was added and the precipitate was filtered and purified by chromatography on silica gel (cyclohexane/ethyl acetate: 2/1) to give 3.35 g of the desired product.
    Rt: 1.30 (method AB), (M+H)+: 269
    • 6.01.26.03 1-(5-Methyl-(1, 2, 4) oxadiazol-3-yl)-piperazine hydrochloride
  • Figure imgb0133
  • 20 mL 4 mol/L HCl solution in dioxane was added to 3.35 g 4-(5-methyl-(1, 2, 4) oxadiazol-3-yl)-piperazine-1-carboxylic acid tert-butyl ester dissolved in 20 mL dioxane was stirred over night. The mixture was diluted with diethylether and the precipitate was filtered and washed with diethylether to give 2.5 g of the desired product.
    Rt: 0.72 min (method AB), (M+H)+: 169
    • 6.01.27 1-(4-Methyl-oxazol-2-yl)-piperazine hydrochloride
  • Figure imgb0134
    • 6.01.27.01 4-(4-Methyl-oxazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester
  • Figure imgb0135
  • 17 mL 2 mol/L aqueous sodium hydroxide solution was dropped to 6.7 g 4-cyano-piperazine-1-carboxylic acid tert-butyl ester and 2.5 mL 1-hydroxy-propan-2-one in 10 mL THF. The reaction was stirred 12h at RT and over night at 75°C. The reaction was coolded, water was added and the mixture was diluted with diethylether. The precipitate was filtered to give 1.32 g of the desired product.
    Rt: 1.30 min. (method AB)
    (M+H)+: 269
    • 6.01.27.02 1-(3-Methyl-(1, 2, 4) oxadiazol-5-yl)-piperazine hydrochloride
  • Figure imgb0136
  • 80.9 mL 1 mol/L zinc chloride solution in diethylether was dropped to 11.4 g 4-cyanopiperazine-1-carboxylic acid tert-butyl ester. The reaction was stirred over night at 150°C. The precipitate was filtered and the filtrate was concentrated and purified by chromatography on silica gel (dichlormethane/methanol/ammonia: 9/1/0.1%). Diethylether was added to the residue and the precipitate was filtered to give 1 g of the desired product. The residue was dissolved in diethylether and hydrogen chloride in was added. The precipitate was filttered to give 0.9 g of the desired product.
    Rt: 0.67min (method F)
    (M+H)+: 169
    • 6.01.28 2-Methyl-5, 6-dihydro-4H-pyrrolo [3, 4-d]-oxazole hydroiodide
  • Figure imgb0137
    • 6.01.28.01 1-Benzyl-2, 5-dihydro-1H-pyrrole
  • Figure imgb0138
  • The compound was produced according to patent application EP 18499770 A1 ; yield: 70% Rt: 10.95 min. (method AG) (M+H)+: 161
    • 6.01.28.02 Benzyl-2, 5-dihydro-1H-pyrrole-1-carboxylate
  • Figure imgb0139
  • 43 mL benzyloxycarbonyl chloride in 135 mL dichlormethane was added to 17.6 g 1-benzyl-2,5-dihydro-1H-pyrrole in 135 mL dichlormethane at 0 °C in 60 min. The mixture was stirred 3h at RT and washed with saturated sodium hydrogencarbonate solution. The organic layer was dried and evaporated. The residue was purified by chromatography on silica gel (hexane/ethyl acetate: 5/1) to give 19.7 g of the desired product.
    Rt: 16.50 min. (method AG)
    (M+H)+: 204
    • 6.01.28.03 Benzyl 6-oxa-3-azabicyclo [3.1.0] hexane-3-carboxylate
  • Figure imgb0140
  • The compound was produced according patent application WO2004/99201 A1 ; yield: 89% Rt: 5.36 min. (method AG), (M+H)+: 220
    • 6.01.28.04 Benzyl 3-amino-4-hydroxypyrrolidine-1-carboxylate
  • Figure imgb0141
  • 6.5 g benzyl 6-oxa-3-azabicyclo [3.1.0] hexane-3-carboxylate in 80 mL 33% aqueous ammonia solution was stirred 20h in a closed vessel. The reaction was cooled and extracted with dichlormethane. The organic layer was was washed with sodium chloride solution and evaporated to give 6.1g of the desired product.
    Rt: 2.37min. (method AG)
    (M+H)+: 237
    • 6.01.28.05 Benzyl 3-acetamido-4-hydroxypyrrolidine-1-carboxylate
  • Figure imgb0142
  • 3.24 g acetic anhydride was added to 7.1 g benzyl 3-amino-4-hydroxypyrrolidine-1-carboxylate in 100 mL dichlormethane at 0-5 °C. The mixture was stirred 2h at RT, 100 mL diethylether was added and the mixture was stirred for 15 min. The precipitate was filtered to give 7.6 g of the desired product.
    Rt: 4.14min. (method AG)
    (M+H)+: 279
    • 6.01.28.06 Benzyl3-acetamido-4-oxopyrrolidine-1-carboxylate
  • Figure imgb0143
  • Pyidin-sulphur trioxide in 6.5 mL DMSO was added to 1.34 g benzyl-3-acetamido-4-hydroxypyrrolidine-1-carboxylate and 2.5 mL DIPEA in 8 mL dichlormethane at 0 °C. The reaction was stirred 1h at RT. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and sodium chloride solution and evaporated. The residue was purified by chromatography on silica gel (ethyl acetate) to give 1.1 g of the desired product. (M+H)+: 277
    • 6.01.28.07 2-Methyl-4, 6-dihydro-pyrrolo [3, 4-d] oxazole-5-carboxylic acid benzyl ester
  • Figure imgb0144
  • 8.5 g methoxycarbonylsulfamoyl) triethylammoniumhydroxid was added to 4.7 g benzyl 3-acetamido-4-oxopyrrolidine-1-carboxylate in 180 mL THF. The reaction was stirred 1h at 65 °C and evaporated. The residue was purified on silica gel (hexane/ethyl acetate: 1/1) to give 1.4 g of the desired product.
    Rt: 1.29 min (method Y), (M+H)+: 259
    • 6.01.28.08 2-methyl-5, 6-dihydro-4H-pyrrolo [3, 4-d] oxazole hydroiodide
  • Figure imgb0145
  • 0.6 mL trimethylsilyliodide was added to 400 mg 2-methyl-4, 6-dihydro-pyrrolo [3, 4-d] oxazole-5-carboxylic acid benzyl ester in 30 mL acetonitrile. The reaction was stirred 4h at RT. The solvent was removed to give 390 mg of the desired product.
    Rt: 0.49 min (method AB)
    (M+H)+: 125
    • 6.01.29 5-fluoro-4-methyl-pyridine-2-carboxylic acid methyl ester
  • Figure imgb0146
  • 18 g 2-bromo-5-fluoro-4-methyl-pyridine, 1.5 g 1, 1'-bis (diphenylphosphino) ferrocene dichloropalladium (II) and 18 g sodium acetate was stirred 17 h at 80°C in an atmosphere of 5 bar carbon monoxide. The reaction was filtered and the solvent was removed. Diethylether was added to the residue and the mixture was filtered. The filtrate was evaporated to give 12 g of the desired product.
    Rt: 0.90 min. (method W)
    (M+H)+: 170
  • By using the same synthesis strategy as for 5-fluoro-4-methyl-pyridine-2-carboxylic acid methyl ester the following compound was obtained:
    Example Product MS m/z [M+H] + HPLC Method Rt min
    6.01.30
    Figure imgb0147
         		170 method W 0.87
    • 6.01.31 3-phenyl-6, 7, 8, 9-tetrahydro-5H-1, 2, 7-triaza-benzocycloheptene dihydrochloride
  • Figure imgb0148
    • 6.01.31.01 4-ethoxycarbonylmethyl-5-oxo-azepane-1, 4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester
  • Figure imgb0149
  • 6.7 g potassium carbonate was added to 7 g 5-oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester in 50 mL DMF and stirred at RT. After 30 min 6.1 g ethyl bromoacetate was added and the reaction was stirred at RT over night. The reaction was diluted with water and extracted with ethyl acetate/hexane (1/1). The organic phase was washed with brine, dried and concentrated. The residue was purified by column chromatography on silica gel (15% ethyl acetate in hexane) to give 5.6 g of the desired product.
    (M+H)+= 372
    • 6.01.31.02 4-carboxymethyl-5-oxo-azepane-1-carboxylic acid tert-butyl ester
  • Figure imgb0150
  • 23.3 g sodium hydroxide in 218 mL water was added to 38 g 4-ethoxycarbonylmethyl-5-oxo-azepane-1, 4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester in 155 mL THF. The reaction was stirred over night at RT, THF was removed and the mixture was extracted with dichlormethane. The aqueous part was acidified with 3M HCl to pH 3 at 0 °C. The aqueous solution was extracted with dichloromethane, dried over magnesium sulfate, concentrated under reduced pressure to give 18.2 g of the desired product.
    (M+H)+=272
    • 6.01.31.03 3-oxo-2, 3, 4, 4a, 5, 6, 8, 9-octahydro-1, 2, 7-triaza-benzocycloheptene-7-carboxylic cid tert-butyl ester
  • Figure imgb0151
  • 60 mL acetic acid was added to 16 g 4-carboxymethyl-5-oxo-azepane-l-carboxylic acid tert-butyl ester in 120 mL THF at 5 °C. 14 mL hydrazine hydrate was added to the reaction and the mixture was refluxed over night. After completion of the reaction, volatiles were removed and the residue was basified with sodium carbonate and extracted with chloroform. The organic layer was dried and concentrated under reduced pressure to afford 11 g of the desired product (M+H)+=268
    • 6.01.31.04 3-oxo-2, 3, 5, 6, 8, 9-hexahydro-1, 2, 7-triaza-benzocycloheptene-7-carboxylic acid ert-butyl ester
  • Figure imgb0152
  • 7 g 3-oxo-2, 3, 4, 4a, 5, 6, 8, 9-octahydro-1, 2, 7-triaza-benzocycloheptene-7-carboxylic cid tert-butyl ester was dissolved in 70 mL toluene and 6.7 g manganese dioxide was added to the reaction mixture. It was heated at reflux for 48h. After completion of the reaction, the reaction mixture was diluted with chloroform and filtered through celite. The filtrate was concentrated and purified by column chromatography to afford 5.5 g of the desired product., (M+H)+= 266
    • 6.01.31.05 3-chloro-5, 6, 8, 9-tetrahydro-1, 2, 7-triaza-benzocycloheptene-7-carboxylic acid tert-butyl ester
  • Figure imgb0153
  • 11 g 3-oxo-2, 3, 5, 6, 8, 9-hexahydro-1, 2, 7-triaza-benzocycloheptene-7-carboxylic acid ert-butyl ester in 90 ml phosphor oxychloride was refluxed overnight. The phosphor oxychloride was quenched with 8.7 g sodium carbonate to pH 8 and 100 mL water was added to the reaction mixture. Di-tert.butyl-dicarbonate was added to the reaction mixture and stirred over night. The solution was extracted with 50% ethyl acetate in hexane. The extracted organic layer was dried, concentrated under reduced pressure and purified by column chromatography to afford 8.0 g of the desired product. (M+H)+= 284
    • 6.01.31.06 3-phenyl-5, 6, 8, 9-tetrahydro-1, 2, 7-triaza-benzocycloheptene-7-carboxylic acid tert-butyl ester
  • Figure imgb0154
  • 5 g phenylboronic acid in 30 mL dioxane was added to 3.2 g 3-chloro-5, 6, 8, 9-tetrahydro-1, 2, 7-triaza-benzocycloheptene-7-carboxylic acid tert-butyl ester and 388 mg (1,1'-bis (diphenyl-phosphinoferrocene)palladium(II)dichloride in 50 mL dioxane under argon. The reaction was stirred at 90 °C over night. The mixture was cooled to RT diluted with water and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydroxide and brine. The solvent was removed and the precipitate was purified by column chromatographie to yieled 5.5 g of the desired product. (M+H)+= 325
    • 6.01.31.07 3-phenyl-6, 7, 8, 9-tetrahydro-5H-1, 2, 7-triaza-benzocycloheptene dihydrochloride
  • Figure imgb0155
  • 40 mL hydrogen chloride in dioxane was added to 5.5 g 3-phenyl-5, 6, 8, 9-tetrahydro-1, 2, 7-triaza-benzocycloheptene-7-carboxylic acid tert-butyl ester in 40 mL dioxane at 5 °C. The reaction was stirred over night. The solvent was removed and co-evaporated with ethyl acetate to yield 3.7 g of the desired product. Rt: 4.09 min (method AE), (M+H)+: 226
    • 6.01.32 2-methyl-2, 5, 6, 7, 8, 9-hexahydro-1, 2, 7-triaza-benzocyclohepten-3-one hydrochloride
  • Figure imgb0156
    • 6.01.32.01 2-methyl-3-oxo-2, 3, 4, 4a, 5, 6, 8, 9-octahydro-1, 2, 7-triaza-benzocycloheptene-7-carboxylic acid tert-butyl ester
  • Figure imgb0157
  • 36 mL acetic acid was added to 10.5 g 4-carboxymethyl-5-oxo-azepane-1-carboxylic acid tert-butyl ester in 75 mL THF at 5 °C. 3.1 mL methylhydrazine was added to the mixture and refluxed for 3h. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine. The crude product was purified by column chromatography on silica gel to yield 6.9 g of the desired product. (M+H)+: 282
    • 6.01.32.02 2-methyl-3-oxo-2, 3, 5, 6, 8, 9-hexahydro-1, 2, 7-triaza-benzocycloheptene-7-carboxylic acid tert-butyl ester
  • Figure imgb0158
  • 3g DDQ was added to 2.5 g 2-methyl-3-oxo-2, 3, 4, 4a, 5, 6, 8, 9-octahydro-1, 2, 7-triaza-benzocycloheptene-7-carboxylic acid tert-butyl ester in 25 mL dioxane. The reaction was refluxed for 12h. Then aqueous potassium carbonate solution was added and the mixture was extracted with chloroform. The organic layer was washed with brine. The crude product was purified by column chromatography on silica gel to yield 1.3 g of the desired product. (M+H)+: 280
    • 6.01.32.03 2-Methyl-2, 5, 6, 7, 8, 9-hexahydro-1, 2, 7-triaza-benzocyclohepten-3-one hydrochloride
  • Figure imgb0159
  • 40 mL dioxane solution of hydrogen chloride was added to 5.5 g 3-phenyl-5, 6, 8, 9-tetrahydro-1, 2, 7-triaza-benzocycloheptene-7-carboxylic acid tert-butyl ester in 40 mL dioxane at 5 °C. The reaction was stirred over night. The solvent was removed and co-evaporated with ethyl acetate to yield 3.7 g of the desired product. (M+H)+: 180, Rt: 7.84 min (method AE)
    • 6.01.33 2, 7-dimethyl-5, 6, 7, 8-tetrahydro-4H-thiazolo [4, 5-d] azepine dihydrobromide
  • Figure imgb0160
    • 6.01.33.01 5-bromo-7-methyl-azepan-4-one hydrobromide /3-bromo-7-methyl-azepan-4-one hydrobromide (mixture of isomeres)
  • Figure imgb0161
  • 9.8 mL bromine was added to 30 g 7-methyl-azepan-4-one hydrobromide in 180 mL acetic acid. The reaction was stirred over night at RT. The reaction was evaporated to yield 33 g of the desired product as isomere mixture. Rf: 0.4 (DCM/ MeOH= 20/1), (M+H)+= 206
    • 6.01.33.02 2, 7-dimethyl-5, 6, 7, 8-tetrahydro-4H-thiazolo [4, 5-d] azepine hydrobromide 2, 6-dimethyl-5, 6, 7, 8-tetrahydro-4H-thiazolo [5, 4-c] azepine hydrobromide isomere mixture
  • Figure imgb0162
  • A mixture of 33 g 5-bromo-7-methyl-azepan-4-one hydrobromide and 3-bromo-7-methylazepan-4-one hydrobromide and 8.6 g thioacetamide in 400 mL dry EtOH was refluxed overnight. The reaction mixture was concentrated to give 30 g of the desired product, which was used for the next step without further purification. Rf: 0.2 (DCM/ MeOH= 20/1), (M+H)+= 183
    • 6.01.33.03 2, 7-Dimethyl-4, 5, 7, 8-tetrahydro-thiazolo [4,5-d] azepine-6-carboxylic acid tert-butyl ester
  • Figure imgb0163
  • A mixture of 30 g 2, 7-dimethyl-5, 6, 7, 8-tetrahydro-4H-thiazolo [4, 5-d] azepine hydrobromide and 2, 6-dimethyl-5, 6, 7, 8-tetrahydro-4H-thiazolo [5, 4-c] azepine hydrobromide, 38.5 g di-tert.butyl-dicarbonate and 9.1 g sodium hydroxide in 300 mL water and 500 mL tetrahydrofuran was stirred at RT for 3 h. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated to dryness. The residue was purified by pre-HPLC to give 7.7 g of the desired product. Rf: 0.6 (DCM/MeOH=20/1), (M+H)+= 283
    • 6.01.33.04 2, 7-dimethyl-5, 6, 7, 8-tetrahydro-4H-thiazolo [4, 5-d] azepine dihydrobromide
  • Figure imgb0164
  • 54 ml 4 mol/L HCL in ethyl acetate was added to 7.7 g 2, 7-Dimethyl-4, 5, 7, 8-tetrahydrothiazolo [4,5-d] azepine-6-carboxylic acid tert-butyl ester in 100 mL ethyl acetate. The reaction was stirred 2h at RT and evaporated to give 6.2 g of the desired product.
    Rf: 0.2 (DCM/MeOH=20/1), (M+H)+= 183
    • 6.01.34 phenyl-(6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-d] azepin-2-yl)-amine
  • Figure imgb0165
    • 6.01.34.01 1-benzyl-5-chloro-2, 3, 6, 7-tetrahydro-1H-azepine-4-carbaldehyde hydrochloride
  • Figure imgb0166
  • 77 mL phosphoroxychloride was added to 62 mL DMF at 8-18 °C. 84 mL dichlormethane was added and 50 g 1-benzyl 4-azepanone hydrochloride. The reaction was stirred over night at RT. The mixture was added to 300 mL ice water and extracted with dichlormethane. The organic layer was evaporated to give 23.3 g of the desired product. (M+H)+= 287
    • 6.01.34.02 (7-benzyl-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-d] azepin-2-yl)-phenyl-amine
  • Figure imgb0167
     1g 1-benzyl-5-chloro-2, 3, 6, 7-tetrahydro-1H-azepine-4-carbaldehyde hydrochloride was added to 1g phenylguanidine carbonate salt and 1g sodium ethanolate in 25 mL ethanol. The reaction was stirred 4h at 70 °C. The mixture was filtered over silica gel and the solvent was removed. The residue was purified by chromatography on silica gel (dichlormethane/MeOH/ammonia: 19/1/0.1) to yield 300 mg of the desired product.
    Rf: 0.55 (DCM/ MeOH/ammonia= 19/1/0.1), (M+H)+= 331
    • 6.01.34.03 phenyl-(6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-d] azepin-2-yl)-amine
  • Figure imgb0168
  • 150 mg (7-benzyl-6, 7, 8, 9-tetrahydro-5H-pyrimido [4, 5-d] azepin-2-yl)-phenyl-amine and 20 mg palladium on charcoal in 10 mL was stirred 1day under 3 bar of a hydrogen atmosphere. The mixture was filltered and evaporated to yield 84 mg of the desired product. (M+H)+=241
    • 6.01.35 3-methyl-6, 7, 8, 9-tetrahydro-5H-imidazo [1, 2-a] [1, 4] diazepine dihydrochloride
  • Figure imgb0169
    • 6.01.35.01 5-oxo-[1, 4] diazepane-1-carboxylic acid tert-butyl ester
  • Figure imgb0170
  • 0.38 g trimethyl-oxonium tetrafluoro borate was added to 0.5 g 5-oxo-perhydro-1, 4-diazepine-1-carboxylic acid tert-butyl ester in 15 mL THF. The reaction was stirred over night at RT. The reaction mixture was washed with saturated aqueous sodiumhydrogencarbonate solution and water. The organic layer was dried and evaporated to give 428 mg of the desired product.
    (M+H)+: 229, Rt: 0.82 min (method J)
    • 6.01.35.02 3-methyl-5, 6, 8, 9-tetrahydro-imidazo [1, 2-a] [1, 4] diazepine-7-carboxylic acid tert-butyl ester
  • Figure imgb0171
  • 0.6 mL propargylamin was added to 429 mg 5-oxo-[1, 4] diazepane-1-carboxylic acid tert-butyl ester in 20 mL methanol. The reaction was refluxed 5h and evaporated to give 468 mg of the desired product. (M+H)+: 252, Rt: 0.88 min (method J)
    • 6.01.35.03 3-methyl-6, 7, 8, 9-tetrahydro-5H-imidazo [1, 2-a] [1, 4] diazepine dihydrochloride
  • Figure imgb0172
  • 1.89 g 3-methyl-5, 6, 8, 9-tetrahydro-imidazo [1, 2-a] [1, 4] diazepine-7-carboxylic acid tert-butyl ester was stirred in 40 mL 4 mol/L HCl solution in dioxane over night. The mixture was concentrated to give 1.67 g of the desired product. Rt: 0.62 min (method AC), (M+H)+: 152
    • 6.01.36 N-(2, 3, 4, 5-Tetrahydro-1H-benzo [d] azepin-7-yl)-acetamide
  • Figure imgb0173
    • 6.01.36.01 N-[3-(2,2,2-Trifluoro-acetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl]-acetamide
  • Figure imgb0174
  • 2.75 mL acetanhydride was added to 5 g 3-trifluoracetyl-7-amino-1, 2, 4, 5-tetrahydro-benzo [D] azepine in concentrated acetic acid. The mixture was stirred 17 h at RT, diluted with water and stirred for another 1h at RT. The precipitate was filltered, washed with water and dried to give 5.35 g of the desired product. Rf: 0.46 (DCM/ MeOH= 19/1), (M+H)+= 301
    • 6.01.36.02 N-(2, 3, 4, 5-Tetrahydro-1H-benzo [d] azepin-7-yl)-acetamide
  • Figure imgb0175
  • 29.2 g potassiumcarbonate in 100 mL of water was added to 17.5 g N-[3-(2, 2, 2-Trifluoroacetyl)-2, 3, 4, 5-tetrahydro-1H-benzo[d]azepin-7-yl]-acetamide in 400 mL MeOH and 50 mL THF at 5 °C. The reaction mixture was stirred in the ice bath for 2 h and 2 h at RT. The solvent was removed and the residue was extracted with brine and dichloromethane, the organic fraction was dried and the solvent removed to yield 14.9 g of the desired product.
    Rf: 0.12 (DCM/ MeOH= 9/1), (M+H)+= 205
    • 6.01.37 2-Methoxy-5, 6, 7, 8-tetrahydro-thiazolo [4, 5-d] azepine
  • Figure imgb0176
    • 6.01.37.01 Diazo-acetic acid ethyl ester
  • Figure imgb0177
  • 11.4 g sodium nitrite in water was added to 20 g Amino-acetic acid ethyl ester hydrochloride and 5.88 g sodium acetate in 50 mL water at 0 °C. The reaction was stirred 10 min. at RT. 3 mL of 10% sulfuric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 10% sodium carbonate, dried and evaporated to give 9 g of the desired product. Rf: 0.40 (petrol ether / ethyl acetate= 6/4), (M+H)+= 116
    • 6.01.37.02 5-Oxo-azepane-1, 4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester
  • Figure imgb0178
  • 3 mL boron trifluoride etherate was added to 4 g 4-oxo-piperidine-1-carboxylic acid tert-butyl ester in 30 mL diethyl ether at -30 °C. Then 3.5 g diazo-acetic acid ethyl ester in diethyl ether was added at the same temperature and stirred for 30 min. The reaction was poured in to ice water and the organic layer was seperated, washed with aqueous sodiumcarbonate solution, dried and evaporated to give 3 g of the desired product.
    Rf: 0.20 (petrol ether/ethyl acetate= 6/4), (M+H)+= 286
    • 6.01.37.03 Azepan-4-one hydrochloride
  • Figure imgb0179
  • 20 g 5-Oxo-azepane-1, 4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester was stirred over night at 110 °C in 200 mL 6 M hydrochloric acid. The reaction was concentrated to yield 11 g of the desired product. Rf: 0.20 (dichlormethane/methanol = 9/1), (M+H)+= 114
    • 6.01.37.04 1-Benzyl-azepan-4-one
  • Figure imgb0180
  • 6 mL benzyl bromide was added to 5 g azepane-4-one hydrochloride and 18.5 g potasium carbonate in 50 mL THF and 25 mL water. The mixture was stirred 5h at 50 °C, evporated, diluted with water and extracted with ethyl acetate. The organic layer was evaporated. The residue was purified by chromatographie on silica gel (petrolether/ ethyl acetate:8/2) to give 5 g of the desired product. Rf: 0.40 (hexane/ethyl acetate= 1/1), (M+H)+= 204
    • 6.01.37.05 1-Benzyl-5-bromo-azepan-4-one
  • Figure imgb0181
  • 33% hydrobromic acid in conc. acetic acid and 1.97 g bromine was added to 5 g 1-benzylazepane-4-one in 15 mL conc. acetic acid. The reaction was stirred 2h at RT and completely concentrated under reduced pressure. The residue was diluted with ethyl acetate and refluxed for 1h and crystallized with ethyl acetate to give 4 g of the desired product.
    Rf: 0.40 (hexane/ethyl acetate= 1/1), (M+H)+= 282/84
    • 6.01.37.06 6-Benzyl-5, 6, 7, 8-tetrahydro-thiazolo [4, 5-d] azepine-2-ylamine
  • Figure imgb0182
  • 2.7 g thiourea was added to 5 g 1-benzyl-5-bromo-azepan-4-one in 50 ml ethanol. The reaction was refluxed 5h and concentrated. The residue was diluted with water and extracted with ethyl acetate. The organic layer was concentrated to give 4 g of the desired product.
    Rf: 0.4 (hexane / ethyl acetate= 1/1)
    (M+H)+= 262
    • 6.01.37.07 6-Benzyl-2-chloro-5, 6, 7, 8-tetrahydro-thiazolo [4, 5-d] azepine
  • Figure imgb0183
  • 6 mL hydrochloric acid was added at 0 °C to 6 g 6-benzyl-5, 6, 7, 8-tetrahydro-thiazolo [4, 5-d] azepine-2-ylamine in 80 mL acetonitrile. The reaction was stirred for 15 min. and 1.9 g sodium nitrite was added. After 30 min. 2.75 g copper(I) chloride was added and the mixture was stirred 2h at RT. The reaction was evaporated, water was added and the mixture was extracted with ethyl acetate. The organic layer was evaporated. The residue was purified by chromatographie on silica gel (hexane/ethyl acetate:9/1) to give 4 g of the desired product.
    Rf: 0.6 (hexane / ethyl acetate= 1/1)
    (M+H)+= 281
    • 6.01.37.08 6-Benzyl-2-methoxy-5, 6, 7, 8-tetrahydro-thiazolo [4, 5-d] azepine
  • Figure imgb0184
  • 3.87 g sodium methoxide was added to 4 g 6-Benzyl-2-chloro-5, 6, 7, 8-tetrahydro-thiazolo [4, 5-d] azepine in 40 mL methanol. The reaction was heated to 80°C in a sealed tube. After completion of the reaction the solvent was removed, water was added and extracted with ethyl acetate. The organic layer was evaporated and the residue was purified by chromatographie on silica gel (petrolether/ethyl acetate:8/2) to give 3 g of the desired product.
    Rf: 0.4 (hexane / ethyl acetate= 1/1)
    (M+H)+= 277
    • 6.01.37.09 2-Methoxy-5, 6, 7, 8-tetrahydro-thiazolo [4, 5-d] azepine -6-carboxylic acid 1-chloro-ethyl ester
  • Figure imgb0185
  • 12.5 g 1-chloroethylchloroformic acid was added to 8 g 6-benzyl-2-methoxy-5, 6, 7, 8-tetrahydro-thiazolo [4, 5-d] azepine and 24 mL DIPEA in 80 mL ethyl acetate at 0 °C. The reaction was stirred 3h at RT and evaporated to give 7 g of the desired product. Rf: 0.6 (hexane/ethyl acetate= 1/1), (M+H)+= 293
    • 6.01.37.10 2-Methoxy-5, 6, 7, 8-tetrahydro-thiazolo [4, 5-d] azepine
  • Figure imgb0186
  • 7 g 2-Methoxy-5, 6, 7, 8-tetrahydro-thiazolo [4, 5-d] azepine-6-carboxylic acid 1-chloro-ethyl ester in 70 mL methanol was heated 15 min. at 40 °C and concentrated. The residue was purified by chromatography (dichlormethane/methanol:6/4) to give 4 g of the desired product.
    Rf: 0.2 (DCM/ MeOH= 1/1), (M+H)+= 187
    • 6.01.38. 5, 6, 7, 8-Tetrahydro-4H-oxazolo [4, 5-d] azepin-2-ylamine
  • Figure imgb0187
  • 6.6 g urea was added to 6 g 5-bromo-azepan-4-one hydrobromide and heated 24 h at 70°C. 4 M aqueous sodium hydroxide was added and the mixture was extracted with chloroform and ethyl acetate. The combined organic layers were evaporated to give 800 mg of the desired product. Rt: 0.39 min (method B), (M+H)+: 154
    • 6.01.39 11-Methyl-2, 3, 4, 5-tetrahydro-1H-azepino [4, 5-b] quinoline
  • Figure imgb0188
  • 110 g azepin-4-on hydrochloride and 99.5 g 2-aminoacetophenone was refluxed for 2 days in 1.5 L 2 M aqueous hydrochloride acid. The mixture was coolded to RT, 2 M aqueous sodium hydroxyde solution was added and the mixture was extracted with chloroform .The organic layer was dried and evaporated. The residue was purified by chromatographie on silica gel (100 % methanol) to yield 64 g of the desired product. Rf: 0.1 (methanol), (M+H)+: 213
    • 6.01.40. 2-Methyl-5, 6, 7, 8-tetrahydro-4H-oxazolo [4, 5-d] azepine hydrochloride
  • Figure imgb0189
    • 6.01.40.01 N-benzyl-N-(but-3-enyl)-but-3-en-1-amine
  • Figure imgb0190
  • 12 g Benzylamine and 25 g 4-bromo-1-buten were added to a suspension of 46 g potassium carbonate in 150 mL DMF and the mixture was heated at 50 °C for 16 h. The reaction mixture was cooled to RT, diluted with ethyl acetate, washed with water and brine, dried, concentrated, and purified by chromatographie on silica gel (hexane/ ethyl acetate 50:1) to yield 18.3 g of the desired product. (M+H)+: 230
    • 6.01.40.02 benzyl dibut-3-enylcarbamate
  • Figure imgb0191
  • 11.2 mL benzylchloroformate was added to 14 g N-benzyl-N-(but-3-enyl)-but-3-en-1-amine in 100 mL toluene at 0 °C. After being heated at 70 °C for 3 h, the reaction mixture was cooled to RT, basified with saturated aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate, washed with brine, dried, concentrated, and purified by chromatographie on silica gel (hexane/ ethyl acetate 20:1) to yield 16.8 g of the desired product. (M+H)+: 274
    • 6.01.40.03 benzyl 2, 3, 6, 7-tetrahydro-1H-azepine-1-carboxylate
  • Figure imgb0192
  • 0.15 g Grubb's 2 catalyst was added to a solution of 8 g benzyl dibut-3-enylcarbamate in 680 mL toluene and heated at 50 °C for 5 h. The solvent was removed and the residue was purified by chromatographie on silica gel (ethyl acetate/hexane 1:5) to yield 6.6 g of the desired product. (M+H)+: 232
    • 6.01.40.04 benzyl 8-oxa-4-azabicyclo [5.1.0] octane-4-carboxylate
  • Figure imgb0193
  • 18 g m-chloroperbenzoic acid was added to 10 g benzyl 2, 3, 6, 7-tetrahydro-1H-azepine-1-carboxylate in 250 ml dichloromethane at 0 °C in several portions. The mixture was allowed to warm to RT over 2 h. 1 L ethyl acetate was added and the solution was extracted with aqueous sodium bicarbonate, 1N aqueous sodium hydroxide and brine. The organic layer was evaporated and the residue was purified by chromatographie on silica gel (ethyl acetae/hexanes 1:5) to yield 10.4 g of the desired product.
    • 6.01.40.05 4-Amino-5-hydroxy-azepane-1-carboxylic acid benzyl ester
  • Figure imgb0194
  • 3 g benzyl 8-oxa-4-azabicyclo [5.1.0] octane-4-carboxylate in 70 mL 30% aqueous ammonia was stirred at 65 °C in a sealed vessel overnight. The reaction was extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate filtered and concentrated to yield 3.1 g of the desired product. (M+H)+: 265
    • 6.01.40.06 4-Acetylamino-5-hydroxy-azepane-1-carboxylic acid benzyl ester
  • Figure imgb0195
  • 3 mL acetic anhydride was added to 8.4 g benzyl 4-amino-5-hydroxy-azepane-1-carboxylic acid benzyl ester in 115 ml dichloromethane at 0 °C. After 1 h at RT, saturated sodium bicarbonate was added. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with brine, dried over sodium sulphate, filtered and concentrated. The residue was purified by chromatographie on silica gel (ethyl acetate/hexane 2:1) to yield 4.5 g of the desired product. (M+H)+: 307
    • 6.01.40.07 4-Acetylamino-5-oxo-azepane-1-carboxylic acid benzyl ester
  • Figure imgb0196
  • 11 g Dess Martin Periodane was added to 6.2 g 4-acetylamino-5-hydroxy-azepane-1-carboxylic acid benzyl ester in 100 mL dichloromethane and stirred for 1 h at RT. The mixture was diluted with dichloromethane and washed with 2 mol/L sodium hydroxide solution. The organic layere was washed with brine, dried and concentrated. The residue was purified by chromatographie on silica gel (EtOAc) to yield 5.5 g of the desired product. (M+H)+: 305
    • 6.01.40.08 Benzyl 2-methyl-4, 5, 7, 8-tetrahydrooxazolo [4, 5-d] azepine-6-carboxylate
  • Figure imgb0197
  • 3 g 4-acetylamino-5-oxo-azepane-1-carboxylic acid benzyl ester in 100 mL tetrahydrofuran and 3.8 g (methoxycarbonylsulfamoyl) triethylammonium hydroxide were heated in a sealed tube at 75 °C for 1h. The solvent was evaporated and the residue was purified by chromatographie on silica gel (ethyl acetate/ hexane 1:2) to yield 23 g of the desired product. (M+H)+: 287
    • 6.01.40.09 2-Methyl-5, 6, 7, 8-tetrahydro-4H-oxazolo [4, 5-d] azepine hydrochloride
  • Figure imgb0198
  • A solution of 25 g of benzyl 2-methyl-4, 5, 7, 8-tetrahydrooxazolo [4, 5-d] azepine-6-carboxylate in 500 ml 2-propanol was stirred under hydrogen atmosphere (1 atm) in the presence of 450 mg of 5% palladium/charcoal (50% water) at RT overnight. After filtration over celite the filtrate was concentrated. The residue was diluted in a mixture of dichloromethane and diethylether and 2 mol/L hydrochloric acid in diethylether was added. The precipitate was filtered and dried to yield 15.5 g of the desired product. Rt: 0.86 min (method F), (M+H)+: 153
    • 6.02. Synthesis of pyrazol-lyl-acids 6.02.01.01 1, 3-Bis-(4-fluoro-phenyl)-1, 3- propandione
  • Figure imgb0199
  • 9.27 g KOtBu was added to 109 mg 18-Krone-6 and 5 mL 4-fluoracetophenone in 150 mL THF. After 30 min at RT 10.7 g 4-fluoro-benzoic acid methyl ester was added and stirred for 3 h at RT. The reaction was decomposed with water and filtered, the filtrate was concentrated and the residue was purified by chromatography on silica gel (cyclohexane/EE: 98:2). The solvent was removed and 3.9 g of the desired compound was obtained. (M+H)+: 261. 1H-NMR ,DMSO 8,30-8,23 (m,3H, 3/CH), 8,10-8,01 (m, 1H, CH), 3,88-3,85 (s, 1H, CH2)
  • By using the same synthesis strategy as for 1, 3-Bis-(4-fluoro-phenyl)-1, 3- propandione the following compounds were obtained:
    Examples Product MS m/z [M+H] + HPLC Method Rt min
    6.02.01.02
    Figure imgb0200
         		209 method C 1.05
    6.02.01.03
    Figure imgb0201
         		195 method C 1.00
    6.02.01.04
    Figure imgb0202
         		221 method J 1.48
    6.02.01.05
    Figure imgb0203
         		239 1H-NMR : DMSO 6,60-6,56 (s,1H,CH), 2,71-2,63 (m,1H,CH), 1,18-1,15 (d,6H,2/CH3)
    6.02.01.06
    Figure imgb0204
         		223 method J 1.59
    6.02.01.07
    Figure imgb0205
         		243 method D 1.08
    6.02.01.08
    Figure imgb0206
         		262 method D 1.09
    6.02.01.09
    Figure imgb0207
         		225 method T 1.20
    6.02.01.10
    Figure imgb0208
         		191 method U 0.81
    6.02.01.11
    Figure imgb0209
         		205 method U 0.86
    6.02.01.12
    Figure imgb0210
         		195 method S 1.20
    6.02.01.13
    Figure imgb0211
         		257 method I 1.16
    6.02.01.14
    Figure imgb0212
         		211/13 method U 0.89
    6.02.01.15
    Figure imgb0213
         		195 method S 1.20
    6.02.01.16
    Figure imgb0214
         		240 method S 1.02
    6.02.01.17
    Figure imgb0215
         		259 method W 1.69
    6.02.01.18
    Figure imgb0216
         		258 method W 1.63
    6.02.01.19
    Figure imgb0217
         		258 Method W 1.64
    6.02.01.20
    Figure imgb0218
         		239 method T 1.56
    6.02.01.21
    Figure imgb0219
         		224 method AB 0.94
    6.02.01.22
    Figure imgb0220
         		209 method A 0.96
    6.02.01.23
    Figure imgb0221
         		269 method R 1.66
    6.02.01.24
    Figure imgb0222
         		292 method AB 0.97
    6.02.01.25
    Figure imgb0223
         		257 method A 1.05
    6.02.01.26
    Figure imgb0224
         		275 method A 1.00
    • 6.02.01 .21 1-(4-fluoro-3-mehyl-phenyl)-3-phenyl-1, 3-propanedione
  • Figure imgb0225
    • 6.02.01.09 1-(4-fluoro-3-mehyl-phenyl)-3-phenyl-1, 3-propanedione
  • 17.3 g KOtBu was dissolved in 500 mL THF and 9 mL acetophenone was added. After 15 min at RT 25.9 g 4-fluoro-3-mehyl-benzoic acid methyl ester was added and stirred for 3 h at RT. The solvent was removed and the residue was purified by chromatography on silica gel (cyclohexane/EE: 98:2). After combination of the desired fractions and removal of the solvent 19.3 g of the desired compound was obtained. (M+H)+: 257
  • By using the same synthesis strategy as for 1-(4-fluoro-3-mehyl-phenyl)-3-phenyl-1, 3-propanedione the following compounds were obtained:
    Examples Product MS m/z [M+H] + HPLC Method Rt min
    6.02.01.22
    Figure imgb0226
         		223 method I 1.03
    6.02.01.23
    Figure imgb0227
         		221 method J 1.53
    6.02.01.24
    Figure imgb0228
         		235 1H-NMR: 6.48(s,1H,CH), 3.88(s,3H,CH3), 2.20(s,3H,CH3)
    6.02.01.25
    Figure imgb0229
         		263 method J 1.73
    6.02.01.26
    Figure imgb0230
         		261 method J 1.67
    6.02.01.27
    Figure imgb0231
         		223 method I 1.03
    6.02.01.28
    Figure imgb0232
         		209 method I 1.45
    6.02.01.29
    Figure imgb0233
         		253 method I 1.06
    6.02.01.30
    Figure imgb0234
         		253 method W 1.50
    6.02.01.31
    Figure imgb0235
         		240 method I 1.02
    6.02.01.32
    Figure imgb0236
         		237 method W 1.67
    6.02.01.33
    Figure imgb0237
         		254 method I 0.98
    6.02.01.34
    Figure imgb0238
         		205 method U 0.89
    6.02.01.35
    Figure imgb0239
         		254 method I 0.98
    6.02.01.36
    Figure imgb0240
         		223 method W 1.63
    6.02.01.37
    Figure imgb0241
         		273 method I 1.00
    6.02.01.38
    Figure imgb0242
         		250 method Y 1.58
    6.02.01.39
    Figure imgb0243
         		202 method Y 1.38
    • 6.02.02.01 3,5-Bis-(4-fluoro-phenyl)-1H-pyrazole
  • Figure imgb0244
  • 3.9 g 1, 3-Bis-(4-fluoro-phenyl)-1, 3- propandione was dissolved in 45 mL of a solution of 1 N hydrazine in THF and stirred for 2 h at 75 °C. The solvent was removed to give 3.6 g of the desired compound. Rt: 1.03 min (method D), (M+H)+: 257
  • By using the same synthesis strategy as for 3, 5-Bis-(4-fluoro-phenyl)-1H-pyrazole the following compounds were obtained:
    Examples Product MS m/z [M+H]+ HPLC Method Rt min
    6.02.02.02
    Figure imgb0245
         		253 method D 1.07
    6.02.02.03
    Figure imgb0246
         		206 method C 0.93
    6.02.02.04
    Figure imgb0247
         		191 method C 0.87
    6.02.02.05
    Figure imgb0248
         		219 method I 0.93
    6.02.02.06
    Figure imgb0249
         		217 method J 1.38
    6.02.02.07
    Figure imgb0250
         		217 method J 1.27
    6.02.02.08
    Figure imgb0251
         		231 method J 1.54
    6.02.02.09
    Figure imgb0252
         		259 method J 1.39
    6.02.02.10
    Figure imgb0253
         		335 method J 1.35
    6.02.02.11
    Figure imgb0254
         		257 method J 1.51
    6.02.02.12
    Figure imgb0255
         		219 method J 1.44
    6.02.02.13
    Figure imgb0256
         		240 method D 0.97
    6.02.02.14
    Figure imgb0257
         		258 method D 0.95
    6.02.02.15
    Figure imgb0258
         		221 method S 1.10
    6.02.02.16
    Figure imgb0259
         		219 method I 0.93
    6.02.02.17
    Figure imgb0260
         		205 method T 1.26
    6.02.02.18
    Figure imgb0261
         		187 method T 1.20
    6.02.02.19
    Figure imgb0262
         		201 method U 0.71
    6.02.02.20
    Figure imgb0263
         		249 method I 1.06
    6.02.02.21
    Figure imgb0264
         		191 method S 1.10
    6.02.02.22
    Figure imgb0265
         		253 method I 0.99
    6.02.02.23
    Figure imgb0266
         		249 method U 0.76
    6.02.02.24
    Figure imgb0267
         		207 method U 0.81
    6.02.02.25
    Figure imgb0268
         		236 method I 0.68
    6.02.02.26
    Figure imgb0269
         		233 method W 1.52
    6.02.02.27
    Figure imgb0270
         		250 method I 0.64
    6.02.02.28
    Figure imgb0271
         		201 method U 0.78
    6.02.02.29
    Figure imgb0272
         		308 method I 0.69
    6.02.02.30
    Figure imgb0273
         		219 method W 1.45
    6.02.02.31
    Figure imgb0274
         		236 method S 0.84
    6.02.02..32
    Figure imgb0275
         		255 method W 1.50
    6.02.02.33
    Figure imgb0276
         		269 method Z 0.76
    6.02.02.34
    Figure imgb0277
         		254 method W 1.35
    6.02.02.35
    Figure imgb0278
         		254 method W 1.39
    6.02.02.36
    Figure imgb0279
         		198 method Y 1.24
    6.02.02.37
    Figure imgb0280
         		246 method Y 1.41
    6.02.02.38
    Figure imgb0281
         		235 method U 0.85
    6.02.02.39
    Figure imgb0282
         		220 method AB 0.78
    6.02.02.40
    Figure imgb0283
         		205 method T 0.86
    6.02.02.41
    Figure imgb0284
         		265 method Y 1.51
    6.02.02.42
    Figure imgb0285
         		288 method AB 0.85
    6.02.02.43
    Figure imgb0286
         		253 method Y 0.97
    6.02.02.44
    Figure imgb0287
         		271 method Y 0.95
    • 6.02.02.39 5-phenyl-1H-pyrazole-3-carboxylic acid methyl ester
  • Figure imgb0288
  • 983 mg hydrazine acetate was added to 2 g 2, 4-Dioxo-4-phenyl-butyric acid methyl ester in 10 mL concentrated acetic acid. The mixture was stirred over night at RT. Then water was added. The precipitate was filtered, stirred with diisopropylether and again filtered to give 1.3 g desired product. Rt: 1.39 min (method O), (M+H)+: 203
    • 6.02.03.01 3-(4-fluoro-3-mehyl-phenyl)-5-phenyl-pyrazol-1-yl-acetic acid methyl ester
  • Figure imgb0289
  • 3.6 g 3,5-Bis-(4-fluoro-phenyl)-1H-pyrazole, 8.8 g K2CO3 and 1.34 mL 2-bromoacetic acid methyl ester were dissolved in 100 mL acetone and stirred over night under reflux. K2CO3 was filtered and the solvent was removed. The residue was purified by HPLC (method 1) to yield 2.6 g of the desired product.
  • By using the same synthesis strategy as for 3-(4-fluoro-3-mehyl-phenyl)-5-phenyl-pyrazol-1-yl-acetic acid methyl ester the following compounds were obtained:
    Examples Product MS m/z [M+H] + HPLC Method Rt min
    6.02.03.02
    Figure imgb0290
         		325 method I 0.97
    6.02.03.03
    Figure imgb0291
         		277 method C 0.98
    6.02.03.04
    Figure imgb0292
         		263 method C 0.92
    6.02.03.05
    Figure imgb0293
         		291 method I 0.97
    6.02.03.06
    Figure imgb0294
         		289 method J 1.41
    6.02.03.07
    Figure imgb0295
         		289 method J 1.36
    6.02.03.08
    Figure imgb0296
         		289 method J 1.54
    6.02.03.09
    Figure imgb0297
         		331 method J 1.62
    6.02.03.10
    Figure imgb0298
         		307 method L 1.39
    6.02.03.11
    Figure imgb0299
         		329
    6.02.03.12
    Figure imgb0300
         		291 method J 1.47
    6.02.03.13
    Figure imgb0301
         		312 method D 0.99
    6.02.03.14
    Figure imgb0302
         		330 method D 1.01
    6.02.03.15
    Figure imgb0303
         		293 method S 1.20
    6.02.03.16
    Figure imgb0304
         		291 method I 0.97
    6.02.03.17
    Figure imgb0305
         		291 method T 1.33
    6.02.03.18
    Figure imgb0306
         		259 method U 0.81
    6.02.03.19
    Figure imgb0307
         		273 method T 1.42
    6.02.03.20
    Figure imgb0308
         		321 method I 1.07
    6.02.03.21
    Figure imgb0309
         		263 method V 1.20
    6.02.03.22
    Figure imgb0310
         		325 method I 0.97
    6.02.03.23
    Figure imgb0311
         		321 method U 0.80
    6.02.03.24
    Figure imgb0312
         		279 method U 1.44
    6.02.03.25
    Figure imgb0313
         		308 method I 0.66
    6.02.03.26
    Figure imgb0314
         		305 method W 1.56
    6.02.03.27
    Figure imgb0315
         		322 method I 0.64
    6.02.03.28
    Figure imgb0316
         		273 method W 1.50
    6.02.03.29
    Figure imgb0317
         		322 method I 0.71
    6.02.03.30
    Figure imgb0318
         		291 method W 1.53
    6.02.03.31
    Figure imgb0319
         		308 method V 0.85
    6.02.03.32
    Figure imgb0320
         		327 method W 1.55
    6.02.03.33
    Figure imgb0321
         		341 method AA 0.79
    6.02.03.34
    Figure imgb0322
         		326 method W 1.34
    6.02.03.35
    Figure imgb0323
         		326 method W 1.38
    6.02.03.36
    Figure imgb0324
         		270 method AC 1.26
    6.02.03.37
    Figure imgb0325
         		318 method AB 1.39
    6.02.03.38
    Figure imgb0326
         		307 method X 1.53
    6.02.03.39
    Figure imgb0327
         		277 method AD 0.90
    6.02.03.40
    Figure imgb0328
         		292 method AB 0.82
    6.02.03.41
    Figure imgb0329
         		360 method AB 0.86
    6.02.03.43
    Figure imgb0330
         		337 method AB 1.51
    6.02.03.44
    Figure imgb0331
         		325 method AB 0.98
    6.02.03.45
    Figure imgb0332
         		343
    • 6.02.04.01 (3, 5-Bis-(4-fluoro-phenyl)-pyrazol-1-yl)-acid
  • Figure imgb0333
  • 3.6 g of 3-(4-fluoro-3-mehyl-phenyl)-5-phenyl-pyrazol-1-yl-acetic acid methyl ester was dissolved in 20 mL dioxane and a solution of 292 mg LiOH in 3 mL of water was added. The mixture was stirred over the weekend at RT. The solvent was removed and the residue was dissolved in 2M HCl and stirred for 2h. The solvent was removed to yield 2.4 g of the product. Rt: 1.43 (method E), (M+H)+: 315
  • By using the same synthesis strategy as for (3, 5-Bis-(4-fluoro-phenyl)-pyrazol-1-yl)-acid the following compounds were obtained:
    Examples Product MS m/z [M+H]+ HPLC Method Rt min
    6.02.04.02
    Figure imgb0334
         		311 method D 1.05
    6.02.04.03
    Figure imgb0335
         		263 method C 0.93
    6.02.04.04
    Figure imgb0336
         		249 method C 0.87
    6.02.04.05
    Figure imgb0337
         		277 method I 0.90
    6.02.04.06
    Figure imgb0338
         		275 method J 1.05
    6.02.04.07
    Figure imgb0339
         		275 method J 1.30
    6.02.04.08
    Figure imgb0340
         		289 method J 1.39
    6.02.04.09
    Figure imgb0341
         		317 method J 1.58
    6.02.04.10
    Figure imgb0342
         		293 method N 1.04
    6.02.04.11
    Figure imgb0343
         		315 1H-NMR: 6.57(s,1H,CH), 4.95(s,2H,CH2), 3.80(s,3H,CH3)
    6.02.04.12
    Figure imgb0344
         		277 method J 1.45
    6.02.04.13
    Figure imgb0345
         		298 method D 0.90
    6.02.04.14
    Figure imgb0346
         		316 method E 1.33
    6.02.04.15
    Figure imgb0347
         		279 method R 1.40
    6.02.04.16
    Figure imgb0348
         		277 method I 0.90
    6.02.04.17
    Figure imgb0349
         		263 method U 0.78
    6.02.04.18
    Figure imgb0350
         		245 method T 1.25
    6.02.04.19
    Figure imgb0351
         		259 method T 1.32
    6.02.04.20
    Figure imgb0352
         		307 method I 0.97
    6.02.04.21
    Figure imgb0353
         		249 method V 1.20
    6.02.04.22
    Figure imgb0354
         		311 method I 0.95
    6.02.04.23
    Figure imgb0355
         		307 method U 0.75
    6.02.04.24
    Figure imgb0356
         		265 method W 1.38
    6.02.04.25
    Figure imgb0357
         		294 method I 0.65
    6.02.04.26
    Figure imgb0358
         		291 method U 0.85
    6.02.04.27
    Figure imgb0359
         		308 method I 0.65
    6.02.04.28
    Figure imgb0360
         		259 method W 1.41
    6.02.04.29
    Figure imgb0361
         		308 method Y 0.91
    6.02.04.30
    Figure imgb0362
         		277 method W 1.45
    6.02.04.31
    Figure imgb0363
         		294 method S 0.80
    6.02.04.32
    Figure imgb0364
         		313 method W 1.51
    6.02.04.33
    Figure imgb0365
         		327 method I 0.87
    6.02.04.34
    Figure imgb0366
         		312 method W 1.26
    6.02.04.35
    Figure imgb0367
         		312 method W 1.30
    6.02.04.36
    Figure imgb0368
         		256 method AB 0.88
    6.02.04.37
    Figure imgb0369
         		304 method AB 1.02
    6.02.04.38
    Figure imgb0370
         		293 method U 0.97
    6.02.04.39
    Figure imgb0371
         		263 method Y 0.86
    6.02.04.40
    Figure imgb0372
         		278 method AB 0.76
    6.02.04.41
    Figure imgb0373
         		346 method AB 0.81
    6.02.04.42
    Figure imgb0374
         		323 method M 1.46
    6.02.04.43
    Figure imgb0375
         		311 method M 0.95
    6.02.04.44
    Figure imgb0376
         		329 method M 0.68
    • 7. Synthesis of target componds 7.01.001 2-(3, 5-diphenyl-pyrazol-1-yl)-1-(4-(5-chloro-pyrimidin-2-yl)-1-piperidinyl)-ethanon
  • Figure imgb0377
  • 28 mg (3, 5-diphenyl-pyrazol-1-yl)-acetic acid was dissolved in 2 mL DMF and 26 mg DIPEA and 32 mg TBTU were added to this solution and the reaction was stirred for 5 minutes at RT. The mixture was added to 20 mg 5-chloro-2-piperidin-4-ylpyrimidine and stirred for 2h. The reaction was cleaned by RP- chromatographie (methanol/water, 0.1%NH3) to yield 11 mg of the desired compound. Rt: 2.38 (method A), (M+H)+: 458
  • By using the same synthetic strategy as for 2-(3, 5-diphenyl-pyrazol-1-yl)-1-(4-(5-chloro-pyrimidin-2-yl)-1-piperidinyl)-ethanon the following compounds were obtained:
    Examples Product MS m/z [M+H] + HPLC Method Rt min
    7.01.002
    Figure imgb0378
         		399 method B 2.15
    7.01.003
    Figure imgb0379
         		444 method A 2.09
    7.01.004
    Figure imgb0380
         		410 method B 2.33
    7.01.005
    Figure imgb0381
         		401 method A 2.35
    7.01.006
    Figure imgb0382
         		398 method A 2.19
    7.01.007
    Figure imgb0383
         		424 method B 2.37
    7.01.008
    Figure imgb0384
         		438 method B 2.39
    7.01.009
    Figure imgb0385
         		412 method A 2.41
    7.01.010
    Figure imgb0386
         		462 method B 2.46
    7.01.011
    Figure imgb0387
         		467 method A 2.31
    7.01.012
    Figure imgb0388
         		499 method A 2.33
    7.01.013
    Figure imgb0389
         		515 method A 2.36
    7.01.014
    Figure imgb0390
         		455 method A 2.32
    7.01.015
    Figure imgb0391
         		424 method A 2.44
    7.01.016
    Figure imgb0392
         		464 method A 2.40
    7.01.017
    Figure imgb0393
         		415 method B 1.69
    7.01.018
    Figure imgb0394
         		424 method B 2.35
    7.01.019
    Figure imgb0395
         		455 method A 2.31
    7.01.020
    Figure imgb0396
         		467 method A 2.27
    7.01.021
    Figure imgb0397
         		472 method A 2.31
    7.01.022
    Figure imgb0398
         		452 method A 2.39
    7.01.23
    Figure imgb0399
         		430 method G 1.86
    7.01.024
    Figure imgb0400
         		430 method A 2.40
    7.01.025
    Figure imgb0401
         		509 method B 2.42
    7.01.026
    Figure imgb0402
         		486 method A 2.37
    7.01.027
    Figure imgb0403
         		412 method A 2.39
    7.01.028
    Figure imgb0404
         		501 method A 2.34
    7.01.029
    Figure imgb0405
         		438 method A 2.37
    7.01.030
    Figure imgb0406
         		466 method A 2.40
    7.01.031
    Figure imgb0407
         		419 method B 2.29
    7.01.032
    Figure imgb0408
         		463 method B 2.45
    7.01.033
    Figure imgb0409
         		429 method B 1.83
    7.01.034
    Figure imgb0410
         		455 method A 2.31
    7.01.035
    Figure imgb0411
         		467 method A 2.34
    7.01.036
    Figure imgb0412
         		423 method A 1.99
    7.01.037
    Figure imgb0413
         		499 method A 2.33
    7.01.038
    Figure imgb0414
         		401 method A 2.32
    7.01.039
    Figure imgb0415
         		428 method A 2.46
    7.01.040
    Figure imgb0416
         		394 method A 2.40
    7.01.041
    Figure imgb0417
         		487 method A 2.31
    7.01.042
    Figure imgb0418
         		499 method A 2.36
    7.01.043
    Figure imgb0419
         		430 method K 1.27
    7.01.044
    Figure imgb0420
         		429 method A 2.34
    7.01.045
    Figure imgb0421
         		462 method A 2.44
    7.01.046
    Figure imgb0422
         		420 method B 2.29
    7.01.047
    Figure imgb0423
         		508 method A 2.39
    7.01.048
    Figure imgb0424
         		480 method A 2.03
    7.01.049
    Figure imgb0425
         		464 method A 2.02
    7.01.50
    Figure imgb0426
         		464 method AH 2.02
    7.01.051
    Figure imgb0427
         		465 method A 2.17
    7.01.52
    Figure imgb0428
         		430 method AD 0.74
    7.01.053
    Figure imgb0429
         		497 method A 2.44
    7.01.054
    Figure imgb0430
         		429 method AD 0.75
    7.01.055
    Figure imgb0431
         		429 method Q 1.40
    7.01.056
    Figure imgb0432
         		430 method Q 1.27
    7.01.057
    Figure imgb0433
         		399 method Q 1.46
    7.01.058
    Figure imgb0434
         		401 method S 1.47
    7.01.059
    Figure imgb0435
         		399 method S 1.10
    7.01.060
    Figure imgb0436
         		400 method S 1.00
    7.01.061
    Figure imgb0437
         		369 method S 1.20
    7.01.062
    Figure imgb0438
         		371 method S 1.20
    7.01.063
    Figure imgb0439
         		399 method S 1.40
    7.01.064
    Figure imgb0440
         		444 method V 0.88
    7.01.065
    Figure imgb0441
         		422 method AD 0.73
    7.01.066
    Figure imgb0442
         		470 method AD 0.70
    7.01.067
    Figure imgb0443
         		399 method AD 0.70
    7.01.068
    Figure imgb0444
         		400 method AD 0.68
    7.01.069
    Figure imgb0445
         		456 method AD 0.69
    7.01.070
    Figure imgb0446
         		450 method AD 0.71
    7.01.071
    Figure imgb0447
         		398 method AD 0.71
    7.01.072
    Figure imgb0448
         		407 method AD 0.66
    7.01.073
    Figure imgb0449
         		399 method AD 0.74
    7.01.074
    Figure imgb0450
         		427 method AD 0.74
    7.01.075
    Figure imgb0451
         		383 method AD 0.71
    7.01.076
    Figure imgb0452
         		384 method AD 0.73
    7.01.077
    Figure imgb0453
         		383 method AD 0.71
    7.01.078
    Figure imgb0454
         		427 method AD 0.75
    7.01.079
    Figure imgb0455
         		500 method AD 0.79
    7.01.080
    Figure imgb0456
         		533 method AD 0.77
    7.01.081
    Figure imgb0457
         		472 method AF 1.50
    7.01.082
    Figure imgb0458
         		518 method AD 0.76
    7.01.083
    Figure imgb0459
         		470 method AD 0.79
    7.01.084
    Figure imgb0460
         		505 method AD 0.75
    7.01.085
    Figure imgb0461
         		431 method AD 0.78
    7.01.086
    Figure imgb0462
         		444 method AD 0.76
    7.01.087
    Figure imgb0463
         		426 method AD 0.80
    7.01.088
    Figure imgb0464
         		498 method AD 0.79
    7.010.089
    Figure imgb0465
         		447 method AD 0.77
    7.01.090
    Figure imgb0466
         		440 method AD 0.79
    7.01.091
    Figure imgb0467
         		471 method AD 0.77
    7.01.092
    Figure imgb0468
         		518 method AD 0.78
    7.01.093
    Figure imgb0469
         		448 method AD 0.74
    7.01.094
    Figure imgb0470
         		446 method AD 0.75
    7.01.095
    Figure imgb0471
         		455 method AD 0.74
    7.01.096
    Figure imgb0472
         		448 method AD 0.74
    7.01.097
    Figure imgb0473
         		497 method AD 0.77
    7.01.098
    Figure imgb0474
         		382 method AD 0.67
    • 7.02.001 1-(2-Amino-4, 5, 7, 8-tetrahydro-thiazolo (4, 5-d) azepin-6-yl)-2-[3, 5-bis-( 4-fluoro-phenyl)-pyrazol-1-yl]-ethanone
  • Figure imgb0475
  • 100mg (3, 5-bis-(4-fluoro-phenyl)-pyrazol-1-yl)-acetic acid was dissolved in 2 mL DMF. 165 mg PFTU and 170 µL DIPEA were added to this solution and the mixture was stirred for 15 min at RT. Then, 160 mg 5, 6, 7, 8-Tetrahydro-4H-thiazolo (4, 5-d) azepin-2-ylamine hydrobromide was added and the reaction was stirred over night. Then, K2CO3 solution (5%) and CH2Cl2 were added, the organic phase was separated and washed two times with water. The solvent was removed and the residue was purified by HPLC (method 1) to give 78 mg of the desired compound. Rt: 0.80 min (method C), (M+H)+: 466
  • By using the same synthesis strategy as for 1-(2-Amino-4, 5, 7, 8-tetrahydro-thiazolo (4, 5-d) azepin-6-yl)-2-[3,5-bis-(4-fluoro-phenyl)-pyrazol-1-yl]-ethanone the following compounds were obtained:
    7.02.002
    Figure imgb0476
         		488 method A 2.09
    7.02.003
    Figure imgb0477
         		437 method A 2.06
    7.02.004
    Figure imgb0478
         		415 method A 2.04
    7.02.005
    Figure imgb0479
         		472 method A 2.16
    7.02.006
    Figure imgb0480
         		454 method A 2.10
    7.02.007
    Figure imgb0481
         		463 method A 2.13
    7.02.008
    Figure imgb0482
         		441 method A 2.11
    7.02.009
    Figure imgb0483
         		464 method A 2.13
    7.02.010
    Figure imgb0484
         		465 method C 0.95
    7.02.011
    Figure imgb0485
         		437 method C 0.99
    7.02.012
    Figure imgb0486
         		503 method C 0.98
    7.02.013
    Figure imgb0487
         		455 method I 0.83
    7.02.014
    Figure imgb0488
         		454 method I 0.98
    7.02.015
    Figure imgb0489
         		461 method I 0.95
    7.02.016
    Figure imgb0490
         		456 method I 0.97
    7.02.017
    Figure imgb0491
         		488 method I 0.99
    7.02.018
    Figure imgb0492
         		502 method I 1.00
    7.02.019
    Figure imgb0493
         		460 method I 0.94
    7.02.020
    Figure imgb0494
         		433 method I 0.98
    7.02.021
    Figure imgb0495
         		486 method I 0.99
    7.02.022
    Figure imgb0496
         		484 method I 1.00
    7.02.023
    Figure imgb0497
         		462 method I 0.80
    7.02.024
    Figure imgb0498
         		413 method C 0.83
    7.02.025
    Figure imgb0499
         		385 method C 0.87
    7.02.026
    Figure imgb0500
         		414 method C 0.74
    7.02.027
    Figure imgb0501
         		451 method C 0.96
    7.02.028
    Figure imgb0502
         		437 method C 0.92
    7.02.029
    Figure imgb0503
         		399 method I 0.81
    7.02.030
    Figure imgb0504
         		400 method I 0.68
    7.02.031
    Figure imgb0505
         		371 method C 0.81
    7.02.032
    Figure imgb0506
         		465 method I 1.01
    7.02.033
    Figure imgb0507
         		428 method I 0.85
    7.02.034
    Figure imgb0508
         		399 method I 1.01
    7.02.035
    Figure imgb0509
         		425 method M 0.54
    7.02.036
    Figure imgb0510
         		426 method M 0.50
    7.02.037
    Figure imgb0511
         		440 method L 1.30
    7.02.038
    Figure imgb0512
         		425 method J 1.30
    7.02.039
    Figure imgb0513
         		420 method J 1.45
    7.02.040
    Figure imgb0514
         		406 method J 1.44
    7.02.041
    Figure imgb0515
         		463 method J 1.35
    7.02.042
    Figure imgb0516
         		426 method J 1.20
    7.02.043
    Figure imgb0517
         		395 method J 1.35
    7.02.044
    Figure imgb0518
         		434 method J 1.48
    7.02.045
    Figure imgb0519
         		397 method J 1.35
    7.02.046
    Figure imgb0520
         		440 method J 1.31
    7.02.047
    Figure imgb0521
         		439 method J 1.38
    7.02.048
    Figure imgb0522
         		467 method J 1.57
    7.02.049
    Figure imgb0523
         		482 method L 1.46
    7.02.050
    Figure imgb0524
         		468 method J 1.47
    7.02.051
    Figure imgb0525
         		443 method L 1.33
    7.02.052
    Figure imgb0526
         		466 method J 1.37
    7.02.053
    Figure imgb0527
         		503 method J 1.50
    7.02.054
    Figure imgb0528
         		428 method J 1.34
    7.02.055
    Figure imgb0529
         		427 method J 1.44
    7.02.056
    Figure imgb0530
         		448 method C 0.75
    7.02.057
    Figure imgb0531
         		421 method C 0.90
    7.02.058
    Figure imgb0532
         		449 method C 0.67
    7.02.059
    Figure imgb0533
         		439 method C 0.92
    7.02.060
    Figure imgb0534
         		467 method C 0.72
    7.02.061
    Figure imgb0535
         		466 method I 0.82
    7.02.062
    Figure imgb0536
         		444 method L 1.25
    7.02.063
    Figure imgb0537
         		451 method A 2.08
    7.02.064
    Figure imgb0538
         		496 method I 0.73
    7.02.065
    Figure imgb0539
         		447 method U 0.81
    7.02.066
    Figure imgb0540
         		397 method U 0.74
    7.02.067
    Figure imgb0541
         		427 method I 1.00
    7.02.068
    Figure imgb0542
         		452 method I 1.04
    7.02.069
    Figure imgb0543
         		452 method I 1.04
    7.02.070
    Figure imgb0544
         		450 method I 1.06
    7.02.071
    Figure imgb0545
         		450 method I 1.06
    7.02.072
    Figure imgb0546
         		413 method U 0.79
    7.02.073
    Figure imgb0547
         		414 method U 0.72
    7.02.074
    Figure imgb0548
         		410 method U 0.75
    7.02.075
    Figure imgb0549
         		381 method U 0.85
    7.02.076
    Figure imgb0550
         		432 method U 0.88
    7.02.077
    Figure imgb0551
         		434 method U 0.85
    7.02.078
    Figure imgb0552
         		432 method U 0.88
    7.02.079
    Figure imgb0553
         		396 method U 0.70
    7.02.080
    Figure imgb0554
         		367 method U 0.80
    7.02.081
    Figure imgb0555
         		420 method U 0.82
    7.02.082
    Figure imgb0556
         		418 method U 0.84
    7.02.083
    Figure imgb0557
         		409 method U 0.81
    7.02.084
    Figure imgb0558
         		395 method U 0.77
    7.02.085
    Figure imgb0559
         		456 method I 1.00
    7.02.086
    Figure imgb0560
         		457 method I 1.00
    7.02.087
    Figure imgb0561
         		480 method I 1.06
    7.02.088
    Figure imgb0562
         		482 method I 1.04
    7.02.089
    Figure imgb0563
         		480 method I 1.05
    7.02.090
    Figure imgb0564
         		429 method F 1.53
    7.02.091
    Figure imgb0565
         		482 method I 1.04
    7.02.092
    Figure imgb0566
         		434 method U 0.84
    7.02.093
    Figure imgb0567
         		418 method U 0.83
    7.02.094
    Figure imgb0568
         		458 method I 0.86
    7.02.095
    Figure imgb0569
         		461 method I 0.96
    7.02.096
    Figure imgb0570
         		468 method I 0.99
    7.02.097
    Figure imgb0571
         		431 method I 0.99
    7.02.098
    Figure imgb0572
         		459 method I 1.01
    7.02.099
    Figure imgb0573
         		472 method I 1.04
    7.02.100
    Figure imgb0574
         		457 method I 1.02
    7.02.101
    Figure imgb0575
         		484 method I 1.03
    7.02.102
    Figure imgb0576
         		468 method I 1.03
    7.02.103
    Figure imgb0577
         		457 method U 0.77
    7.02.104
    Figure imgb0578
         		458 method U 0.69
    7.02.105
    Figure imgb0579
         		429 method U 0.79
    7.02.106
    Figure imgb0580
         		445 method X 0.85
    7.02.107
    Figure imgb0581
         		411 method X 0.84
    7.02.108
    Figure imgb0582
         		413 method X 0.83
    7.02.109
    Figure imgb0583
         		415 method X 0.77
    7.02.110
    Figure imgb0584
         		416 method X 0.69
    7.02.111
    Figure imgb0585
         		387 method X 0.81
    7.02.112
    Figure imgb0586
         		415 method X 0.73
    7.02.113
    Figure imgb0587
         		415 method X 0.73
    7.02.114
    Figure imgb0588
         		454 method I 1.00
    7.02.115
    Figure imgb0589
         		454 method I 0.97
    7.02.116
    Figure imgb0590
         		444 method I 0.70
    7.02.117
    Figure imgb0591
         		445 method I 0.59
    7.02.118
    Figure imgb0592
         		416 method I 0.72
    7.02.119
    Figure imgb0593
         		441 method U 0.86
    7.02.120
    Figure imgb0594
         		442 method U 0.77
    7.02.121
    Figure imgb0595
         		413 method U 0.88
    7.02.122
    Figure imgb0596
         		458 method I 0.68
    7.02.123
    Figure imgb0597
         		459 method I 0.58
    7.02.124
    Figure imgb0598
         		430 method I 0.71
    7.02.125
    Figure imgb0599
         		381 method U 0.82
    7.02.126
    Figure imgb0600
         		458 method I 0.70
    7.02.127
    Figure imgb0601
         		459 method I 0.61
    7.02.128
    Figure imgb0602
         		430 method I 0.73
    7.02.129
    Figure imgb0603
         		409 method U 0.80
    7.02.130
    Figure imgb0604
         		446 method U 0.90
    7.02.131
    Figure imgb0605
         		441 method U 0.86
    7.02.132
    Figure imgb0606
         		427 method U 0.80
    7.02.133
    Figure imgb0607
         		428 method U 0.71
    7.02.134
    Figure imgb0608
         		473 method I 1.00
    7.02.135
    Figure imgb0609
         		425 method I 0.95
    7.02.136
    Figure imgb0610
         		482 method I 1.04
    7.02.137
    Figure imgb0611
         		434 method I 1.00
    7.02.138
    Figure imgb0612
         		464/466 method X 0.70
    7.02.139
    Figure imgb0613
         		462 method X 0.78
    7.02.140
    Figure imgb0614
         		475 method I 0.98
    7.02.141
    Figure imgb0615
         		427 method I 0.93
    7.02.142
    Figure imgb0616
         		459 method X 0.84
    7.02.143
    Figure imgb0617
         		435 method X 0.82
    7.02.144
    Figure imgb0618
         		461 method X 0.83
    7.02.145
    Figure imgb0619
         		463/465 method X 0.80
    7.02.146
    Figure imgb0620
         		484 method I 1.03
    7.02.147
    Figure imgb0621
         		436 method I 0.99
    7.02.148
    Figure imgb0622
         		477 method I 0.86
    7.02.149
    Figure imgb0623
         		478 method I 0.74
    7.02.150
    Figure imgb0624
         		449 method I 0.91
    7.02.151
    Figure imgb0625
         		476 method I 0.87
    7.02.152
    Figure imgb0626
         		475 method I 0.92
    7.02.153
    Figure imgb0627
         		473 method I 0.93
    7.02.154
    Figure imgb0628
         		399 method I 0.84
    7.02.155
    Figure imgb0629
         		355 method I 0.85
    7.02.156
    Figure imgb0630
         		355 method I 0.85
    7.02.157
    Figure imgb0631
         		412 method U 0.71
    7.02.158
    Figure imgb0632
         		476 method U 0.73
    7.02.159
    Figure imgb0633
         		531 method U 0.84
    7.02.160
    Figure imgb0634
         		475 method U 0.79
    7.02.161
    Figure imgb0635
         		477 method U 0.84
    7.02.162
    Figure imgb0636
         		483 method U 0.80
    7.02.163
    Figure imgb0637
         		427 method U 0.73
    7.02.164
    Figure imgb0638
         		428 method U 0.93
    7.02.165
    Figure imgb0639
         		460 method AB 1.51
    7.02.166
    Figure imgb0640
         		426 method AB 1.49
    7.02.167
    Figure imgb0641
         		412 method AB 1.45
    7.02.168
    Figure imgb0642
         		398 method AB 1.39
    7.02.169
    Figure imgb0643
         		461 method I 0.97
    7.02.170
    Figure imgb0644
         		462 method U 0.68
    7.02.171
    Figure imgb0645
         		463 method U 0.60
    7.02.172
    Figure imgb0646
         		434 method U 0.72
    7.02.173
    Figure imgb0647
         		418 method U 0.70
    7.02.174
    Figure imgb0648
         		462 method U 0.71
    7.02.175
    Figure imgb0649
         		462 method U 0.66
    7.02.176
    Figure imgb0650
         		434 method U 0.69
    7.02.177
    Figure imgb0651
         		418 method U 0.67
    7.02.178
    Figure imgb0652
         		462 method U 0.68
    7.02.179
    Figure imgb0653
         		462 method U 0.68
    7.02.180
    Figure imgb0654
         		462 method U 0.65
    7.02.181
    Figure imgb0655
         		399 method U 0.81
    7.02.182
    Figure imgb0656
         		402 method I 0.95
    7.02.183
    Figure imgb0657
         		404 method I 0.85
    7.02.184
    Figure imgb0658
         		406 method I 0.77
    7.02.185
    Figure imgb0659
         		407 method I 0.65
    7.02.186
    Figure imgb0660
         		378 method I 0.82
    7.02.187
    Figure imgb0661
         		406 method I 0.76
    7.02.188
    Figure imgb0662
         		450 method I 0.91
    7.02.189
    Figure imgb0663
         		454 method I 0.85
    7.02.190
    Figure imgb0664
         		455 method I 0.71
    7.02.191
    Figure imgb0665
         		426 method I 0.89
    7.02.192
    Figure imgb0666
         		454 method I 0.83
    7.02.193
    Figure imgb0667
         		453 method I 0.84
    7.02.194
    Figure imgb0668
         		452 method I 0.89
    7.02.195
    Figure imgb0669
         		461 method I 0.95
    7.02.196
    Figure imgb0670
         		413 method I 0.90
    7.02.197
    Figure imgb0671
         		442 method U 0.78
    7.02.198
    Figure imgb0672
         		443 method U 0.78
    7.02.199
    Figure imgb0673
         		444 method U 0.70
    7.02.200
    Figure imgb0674
         		415 method U 0.81
    7.02.201
    Figure imgb0675
         		468 method U 0.83
    7.02.202
    Figure imgb0676
         		466 method U 0.84
    7.02.203
    Figure imgb0677
         		468 method U 0.83
    7.02.204
    Figure imgb0678
         		466 method U 0.83
    7.02.205
    Figure imgb0679
         		409 method U 0.78
    7.02.206
    Figure imgb0680
         		422 method U 0.82
    7.02.207
    Figure imgb0681
         		411 method U 0.78
    7.02.208
    Figure imgb0682
         		425 method U 0.81
    7.02.209
    Figure imgb0683
         		427 method U 0.76
    7.02.210
    Figure imgb0684
         		426 method U 0.76
    7.02.211
    Figure imgb0685
         		427 method U 0.79
    7.02.212
    Figure imgb0686
         		417 method AB 1.48
    7.02.213
    Figure imgb0687
         		369 method AB 0.91
    7.02.214
    Figure imgb0688
         		383 method AB 1.45
    7.02.215
    Figure imgb0689
         		411 method U 0.78
    7.02.216
    Figure imgb0690
         		462 method U 0.74
    7.02.217
    Figure imgb0691
         		414 method U 0.67
    7.02.218
    Figure imgb0692
         		474 method L 1.47
    7.02.219
    Figure imgb0693
         		426 method L 1.37
    7.02.220
    Figure imgb0694
         		413 method L 1.33
    7.02.221
    Figure imgb0695
         		495 method L 1,36
    7.02.222
    Figure imgb0696
         		467 method L 1.42
    7.02.223
    Figure imgb0697
         		451 method L 1.40
    7.02.224
    Figure imgb0698
         		495 method L 1.41
    7.02.225
    Figure imgb0699
         		495 method L 1.35
    7.02.226
    Figure imgb0700
         		494 method L 1.29
    7.02.227
    Figure imgb0701
         		490 method L 1.43
    7.02.228
    Figure imgb0702
         		442 method L 1.33
    7.02.229
    Figure imgb0703
         		413 method L 1.44
    7.02.230
    Figure imgb0704
         		365 method L 1.32
    7.02.231
    Figure imgb0705
         		445 method I 0.89
    7.02.232
    Figure imgb0706
         		473 method U 0.83
    7.02.233
    Figure imgb0707
         		445 method U 0.84
    7.02.234
    Figure imgb0708
         		496 method I 0,80
    7.02.235
    Figure imgb0709
         		496 method I 0,84
    7.02.236
    Figure imgb0710
         		496 method I 0,79
    7.02.237
    Figure imgb0711
         		468 method I 0,85
    7.02.238
    Figure imgb0712
         		413 method I 0,85
    7.02.239
    Figure imgb0713
         		385 method I 0,90
    7.02.240
    Figure imgb0714
         		473 method U 0.79
    7.02.241
    Figure imgb0715
         		472 method U 0.74
    7.02.242
    Figure imgb0716
         		499 method L 1.55
    7.02.243
    Figure imgb0717
         		451 method L 1.48
    7.02.244
    Figure imgb0718
         		452 method I 0,81
    7.02.245
    Figure imgb0719
         		369 method L
    7.02.246
    Figure imgb0720
         		429 method L 1.45
    7.02.247
    Figure imgb0721
         		428 method I 0,79
    7.02.248
    Figure imgb0722
         		400 method I 0,83
    7.02.249
    Figure imgb0723
         		384 method I 0,81
    7.02.250
    Figure imgb0724
         		461 method I 0,92
    7.02.251
    Figure imgb0725
         		461 method I 0,94
    7.02.252
    Figure imgb0726
         		433 method I 0,97
    7.02.253
    Figure imgb0727
         		417 method I 0,95
    7.02.255
    Figure imgb0728
         		431,12 method K 0,81
    7.02.256
    Figure imgb0729
         		383,1 method K 0,73
    7.02.257
    Figure imgb0730
         		435,12 method K 0,74
    7.02.258
    Figure imgb0731
         		479,15 method K 0,70
    7.02.259
    Figure imgb0732
         		479,13 method K 0,77
    7.02.260
    Figure imgb0733
         		451,1 method K 0,77

Claims (5)

  1. A compound of formula I
    Figure imgb0734
     in which
    R1 represents phenyl, methyl, ethyl, propyl, iso-propyl, cyclopropyl, cyclohexyl,
    Figure imgb0735
    X represents
    Figure imgb0736
    Figure imgb0737
    Figure imgb0738
    Figure imgb0739
    Figure imgb0740
    Figure imgb0741
    Figure imgb0742
    Figure imgb0743
    Figure imgb0744
    Figure imgb0745
    Figure imgb0746
    Figure imgb0747
    Figure imgb0748
    Figure imgb0749
    Figure imgb0750
    Figure imgb0751
    Figure imgb0752
    Figure imgb0753
    Figure imgb0754
    Figure imgb0755
    Figure imgb0756
    Figure imgb0757
    Figure imgb0758
    Figure imgb0759
    Figure imgb0760
    Figure imgb0761
    Figure imgb0762
    Figure imgb0763
    Figure imgb0764
    Figure imgb0765
    Figure imgb0766
    Figure imgb0767
    Figure imgb0768
    Figure imgb0769
    Figure imgb0770
    Figure imgb0771
    Figure imgb0772
    Figure imgb0773
    Figure imgb0774
    Figure imgb0775
    Figure imgb0776
    Figure imgb0777
    Figure imgb0778
    Figure imgb0779
    Figure imgb0780
     the group
    Figure imgb0781
     represents
    Figure imgb0782
    Figure imgb0783
    Figure imgb0784
    Figure imgb0785
    Figure imgb0786
     or a salt thereof, particularly a physiologically acceptable salt thereof.
  2. A compound according to claim 1 selected from the group comprising
    Figure imgb0787
    Figure imgb0788
    Figure imgb0789
    Figure imgb0790
    Figure imgb0791
    Figure imgb0792
    Figure imgb0793
    Figure imgb0794
    Figure imgb0795
    Figure imgb0796
    Figure imgb0797
    Figure imgb0798
    Figure imgb0799
    Figure imgb0800
    Figure imgb0801
    Figure imgb0802
    Figure imgb0803
    Figure imgb0804
    Figure imgb0805
    Figure imgb0806
    Figure imgb0807
    Figure imgb0808
    Figure imgb0809
    Figure imgb0810
    Figure imgb0811
    Figure imgb0812
    Figure imgb0813
    Figure imgb0814
    Figure imgb0815
    Figure imgb0816
    Figure imgb0817
    Figure imgb0818
    Figure imgb0819
    Figure imgb0820
    Figure imgb0821
    Figure imgb0822
    Figure imgb0823
    Figure imgb0824
    Figure imgb0825
    Figure imgb0826
    Figure imgb0827
    Figure imgb0828
    Figure imgb0829
    Figure imgb0830
    Figure imgb0831
    Figure imgb0832
    Figure imgb0833
    Figure imgb0834
    Figure imgb0835
    Figure imgb0836
    Figure imgb0837
    Figure imgb0838
    Figure imgb0839
    Figure imgb0840
    Figure imgb0841
    Figure imgb0842
    Figure imgb0843
    Figure imgb0844
    Figure imgb0845
    Figure imgb0846
    Figure imgb0847
    Figure imgb0848
    Figure imgb0849
    Figure imgb0850
    Figure imgb0851
    Figure imgb0852
    Figure imgb0853
    Figure imgb0854
    Figure imgb0855
    Figure imgb0856
    Figure imgb0857
    Figure imgb0858
    Figure imgb0859
    Figure imgb0860
    Figure imgb0861
    Figure imgb0862
    Figure imgb0863
    Figure imgb0864
    Figure imgb0865
    Figure imgb0866
    Figure imgb0867
    Figure imgb0868
    Figure imgb0869
    Figure imgb0870
    Figure imgb0871
    Figure imgb0872
    Figure imgb0873
    Figure imgb0874
    Figure imgb0875
    Figure imgb0876
    Figure imgb0877
    Figure imgb0878
    Figure imgb0879
    Figure imgb0880
    Figure imgb0881
    Figure imgb0882
    Figure imgb0883
    Figure imgb0884
    Figure imgb0885
    Figure imgb0886
    Figure imgb0887
    Figure imgb0888
    Figure imgb0889
    Figure imgb0890
    Figure imgb0891
    Figure imgb0892
    Figure imgb0893
    Figure imgb0894
    Figure imgb0895
    Figure imgb0896
    Figure imgb0897
    Figure imgb0898
    Figure imgb0899
    Figure imgb0900
    Figure imgb0901
    Figure imgb0902
    Figure imgb0903
    Figure imgb0904
    Figure imgb0905
    Figure imgb0906
    Figure imgb0907
    Figure imgb0908
    Figure imgb0909
    Figure imgb0910
    Figure imgb0911
    Figure imgb0912
    Figure imgb0913
    Figure imgb0914
    Figure imgb0915
    Figure imgb0916
    Figure imgb0917
    Figure imgb0918
    Figure imgb0919
    Figure imgb0920
    Figure imgb0921
    Figure imgb0922
    Figure imgb0923
    Figure imgb0924
    Figure imgb0925
    Figure imgb0926
    Figure imgb0927
    Figure imgb0928
    Figure imgb0929
    Figure imgb0930
    Figure imgb0931
    Figure imgb0932
    Figure imgb0933
    Figure imgb0934
    Figure imgb0935
    Figure imgb0936
    Figure imgb0937
    Figure imgb0938
    Figure imgb0939
    Figure imgb0940
    Figure imgb0941
    Figure imgb0942
    Figure imgb0943
    Figure imgb0944
    Figure imgb0945
    Figure imgb0946
    Figure imgb0947
    Figure imgb0948
    Figure imgb0949
    Figure imgb0950
    Figure imgb0951
    Figure imgb0952
    Figure imgb0953
    Figure imgb0954
    Figure imgb0955
    Figure imgb0956
    Figure imgb0957
    Figure imgb0958
    Figure imgb0959
    Figure imgb0960
    Figure imgb0961
    Figure imgb0962
    Figure imgb0963
    Figure imgb0964
    Figure imgb0965
  3. A compound according to any of the preceding claims for use as a medicament.
  4. A pharmaceutical composition comprising at least one compound according to any of claims 1 to 2 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier.
  5. A compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof for use in the treatment of psychotic disorders including schizophrenia, schizoaffective disorder and substance induced psychotic disorder; cognitive disorders and dementias including age-associated learning and memory impairments or losses, post stroke dementia, deficits in concentration, mild cognitive impairment, the cognitive dysfunction in Alzheimers disease, and the cognitive dysfunction of schizophrenia.
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